Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5]
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Oc1ccccc1)c1ccc(O)cc1O
Yield: 54.5 %

Procedure:
A 1.5 l sulfonating flask equipped with stirrer, condenser, dropping funnel and gas outlet is charged with 154.1 g (1.0 mol) of 2,4-dihydroxybenzoic acid, 141.2 g (1.5 mol) of phenol, 500 ml of toluene and 1 ml of dimethylformamide. 178.5 g (1.5 mol) of thionyl chloride are then added dropwise at an internal temperature of 100°-105° C. over a period of 2.5 hours. The reddish clear solution is then refluxed overnight (110°-115° C.). The toluene and the phenol are distilled off in vacuo, the highly viscous residue (271.5 g) is stirred in 300 ml of 7:3 toluene/cyclohexane, and the product is allowed to crystallize overnight. The precipitate is filtered off with suction while cold (10° C.) and washed with 3×50 ml of 7:3 toluene/cyclohexane. It is dried at 80° C. in vacuo to give 125.5 g (54.4% of theory) of phenyl 2,4-dihydroxybenzoate (m.p. 135°-137° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[N:4]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].C(N(CC)CC)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH:12]=[CH:15][N:16]([CH3:18])[CH3:17])[N:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(C)n1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])c(C=CN(C)C)n1
Temperature: 120 °C
Yield: 99.6 %

Procedure:
To 2-methoxy-5-nitro-6-methylpyridine (29.39 g, 175 mmol) dissolved in 300 mL of N,N-dimethylformamide was added dimethylformamide dimethylacetal (120 mL, 896 mmol) and triethylamine (1 mL). The bright red reaction mixture was heated at 120° C. for 2 hours, then concentrated in vacuo to provide 38.90 g of the title compound as a red solid, which was used in Preparation 13 without further purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]2[CH2:14][CH2:13][CH2:12][C:5]=2[N:6]([CH2:8][C:9]([OH:11])=O)[N:7]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:48][C:49]1[CH:54]=[CH:53][C:52]([N:55]2[C:63]3[CH2:62][CH2:61][CH2:60][NH:59][C:58]=3[CH:57]=[N:56]2)=[CH:51][CH:50]=1>CN(C=O)C.O>[F:48][C:49]1[CH:50]=[CH:51][C:52]([N:55]2[C:63]3[CH2:62][CH2:61][CH2:60][N:59]([C:9](=[O:11])[CH2:8][N:6]4[C:5]5[CH2:12][CH2:13][CH2:14][C:4]=5[C:3]([C:2]([F:1])([F:16])[F:15])=[N:7]4)[C:58]=3[CH:57]=[N:56]2)=[CH:53][CH:54]=1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCC2)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 7.1 %

Procedure:
To a solution 2-[3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-1-yl]acetic acid (83 mg, 0.35 mmol) in DMF (2 mL) was added Et3N (75 μL, 0.525 mmol), HATU (160 mg, 0.42 mmol), followed by 1-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine (77 mg, 0.35 mmol) at room temperature. The resulting solution was then stirred at 50° C. for 30 min. The reaction mixture was then cooled to room temperature, H2O (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined EtOAc layers were dried (MgSO4), filtered, and concentrated in vacuo. Purification by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the desired product as a white powder (0.011 g, 0.025 mmol, 7%). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.6 (m, 2H), 7.35 (t, 2H, J=8.6, 17.6 Hz), 5.38 (s, 2H), 3.77 (m, 2H), 2.85 (t, 2H, J=6.3, 12.5 Hz), 2.66 (m, 4H), 2.53 (m, 2H), 1.97 (m, 2H); MS: (ES) m/z calculated for C21H19F4N5O [M+H]+ 434.2, found 434.1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]#[N:8])[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[N+:19]([O-])=O)=[N:3]1.N.O.S>C(O)C>[NH2:19][C:11]1[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:10]=1[NH:9][C:4]1[C:5]([C:7]#[N:8])=[CH:6][N:2]([CH3:1])[N:3]=1
Reactant: Cn1cc(C#N)c(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])n1
Agent: N
Agent: S
Solvent: CCO
Solvent: O
Product: Cn1cc(C#N)c(Nc2ccc([N+](=O)[O-])cc2N)n1

Procedure:
1-Methyl-3-(2,4-dinitroanilino)pyrazole-4-carbonitrile (2.88 g) was stirred in a mixture of 0.88 ammonia solution (60 ml), water (90 ml) and ethanol (60 ml) under reflux whilst a slow stream of hydrogen sulphide gas was bubbled through for 2 hours. The mixture was cooled, filtered and the residue crystallised from ethyl acetate-n-hexane to give the title compound m.p. 204° C.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[Cl:8][C:9]1[CH:10]=[C:11]([NH:16][C:17]2[C:22]3[C:23]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][C:24]=4[S:30][C:21]=3[N:20]=[CH:19][N:18]=2)[CH:12]=[CH:13][C:14]=1[Cl:15].[CH3:31][NH:32][CH:33]1[CH2:35][CH2:34]1>>[CH:33]1([N:32]([CH3:31])[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:26]2[CH2:27][CH2:28][CH2:29][C:23]3[C:22]4[C:17]([NH:16][C:11]5[CH:12]=[CH:13][C:14]([Cl:15])=[C:9]([Cl:8])[CH:10]=5)=[N:18][CH:19]=[N:20][C:21]=4[S:30][C:24]=3[CH2:25]2)=[O:7])[CH2:35][CH2:34]1
Reactant: O=C(O)/C=C/CBr
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CCCNC4)cc1Cl
Reactant: CNC1CC1
Product: CN(C/C=C/C(=O)N1CCCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1)C1CC1

Procedure:
In analogy to Example 130, the title compound was prepared from (2E)-4-bromobut-2-enoic acid (127 mg, 0.62 mmol), N-(3,4-dichlorophenyl)-6,7,8,9-tetrahydro-5H-pyrimido[5′,4′:4,5]thieno[2,3-c]azepin-4-amine from Example 82A (150 mg, 0.41 mmol) and N-methylcyclopropanamine (116 mg, 1.63 mmol) to yield 21 mg (10%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:17])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1>[Pd].C(O)C.C1COCC1>[NH2:1][C:2]1[C:3]([F:17])=[C:4]([CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(N)c1F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCc1cccc(N)c1F
Reaction time: 8 h

Procedure:
Palladium on carbon (10%) was added to a solution of 1660 mg (7.0 mmol) of tert-butyl (2E)-3-(3-amino-2-fluorophenyl)acrylate in a mixture of 5 ml of ethanol and 3 ml of THF, and the mixture was stirred vigorously at atmospheric pressure under an atmosphere of hydrogen overnight. The reaction mixture was then filtered through kieselguhr and the filter residue was washed repeatedly with ethanol/THF. The combined filtrates were concentrated under reduced pressure and the residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 1350 mg of the target product (80.6% of theory).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C>[Pd].C1C=CC=CC=1>[C:23]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:27])[NH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C1=CC(=Nc2cccc(OCC(=O)O)c2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CCO
Product: CC(C)(C)c1cc(Nc2cccc(OCC(=O)O)c2)cc(C(C)(C)C)c1O
Reaction time: 5 h

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenoxyacetic acid, 250 ml of ethanol and 10 mg of 5% palladium on charcoal catalyst was placed on a Paar apparatus. Hydrogenation was complete after five hours. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to give a thick brown oil. The oil was dissolved in 20 ml of benzene, filtered, diluted with 20 ml of cyclohexane and 10 ml of hexane, and chilled to give 1.4 g of light tan crystalline 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenoxyacetic acid, m.p. 127°-127.5° C. Analysis: Calculated for C22H29NO4 ; % C, 71.1; % H, 7.9; % N, 3.8; Found: % C, 70.3; % H, 7.6; % N, 3.7.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=O.[C:14]([CH2:16]C(O)=O)#[N:15].C1(C)C=CC=CC=1.C([O-])(=O)C.[NH4+]>CN(C)C=O>[CH3:1][C:2]([CH2:5][CH2:6][CH:7]([CH3:13])[CH2:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:3][CH2:16][C:14]#[N:15]
Reactant: N#CCC(=O)O
Reactant: CC(C=O)CCC(C)CC(C)(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=CCC#N)CCC(C)CC(C)(C)C
Temperature: 180 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
438 g (2.38 moles) of 2,5,7,7-tetramethyloctanal, 202 g (2.38 moles) of cyanoacetic acid, 350 ml of toluene, 350 ml of dimethylformamide and 28.5 g of ammonium acetate were heated under a water separator for 4 h, while stirring. Thereafter, the toluene was distilled off and the remaining residue was heated for 2 h at 180° C. The cooled residue was poured onto ice water and 10 extracted with diethyl ether. The organic phase was washed in succession with NaHCO: solution and water and then distilled. 450 g (yield: 91% of theory) of 4,7,9,9-tetramethyldec-3-enenitrile of boiling point 83°-88° C./-.3 mbar were obtained. The fragrance note was waxy, floral and fresh.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[CH2:9]1)C1C=CC=CC=1.[Cl:16]C(OC(Cl)C)=O>C(Cl)Cl>[ClH:16].[CH3:14][C:10]1([CH3:15])[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC1(C)CN(Cc2ccccc2)CCO1
Solvent: ClCCl
Product: CC1(C)CNCCO1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.4 %

Procedure:
Dissolve 4-benzyl-2,2-dimethyl-morpholine (5.67 g, 27.6 mmol) in CH2Cl2 (50 mL) and add 1-chloroethyl chloroformate (4.60 mL, 42.2 mmol) while stirring at room temperature. After 4 h, concentrate the solution and treat the residue with MeOH (60 mL). Heat the mixture at 60° C. for 2 h, then concentrate again. Dissolve the residue in water (125 mL) and wash with tert-butyl methyl ether (125 mL). Concentrate the aqueous layer and dry the resulting residue at 80° C. under vacuum to give the title compound (3.91 g, 93%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.52 (2H, br s), 3.75 (2H, m), 2.89-2.96 (4H, m), 1.25 (6H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][F:16])[CH2:10][C:11](O)=[O:12])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].C(Cl)(=O)C(Cl)=O.C[N:28](C=O)C.N>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][F:16])[CH2:10][C:11]([NH2:28])=[O:12])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(N(CCF)CC(=O)O)cc1C(F)(F)F
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: N#Cc1ccc(N(CCF)CC(N)=O)cc1C(F)(F)F
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 303.3 %

Procedure:
A suspension of N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(2-fluoroethyl)glycine (0.031 g, 0.11 mmol) in anhydrous CH2Cl2 (2 mL), under nitrogen, was cooled in an ice bath and treated with oxalyl chloride (0.017 g, 0.13 mmol) and anhydrous DMF (˜0.001 g). The mixture was heated at 50° C. for 20 min. Upon cooling, the mixture was added into an aqueous solution of ammonia (30%, 10 mL) and stirred heavily for 5 min. The mixture was partitioned between CH2Cl2 (20 mL), water (20 mL) and methanol (5 mL). The aqueous phase was extracted 3 times with CH2Cl2/MeOH (˜10:1). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from CH2Cl2/MeOH to give 0.012 g (40% yield) of the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 7.79 (d, J=8.8 Hz, 1H), 7.52 (bs, 1H), 7.21 (bs, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.8, 2.4 Hz, 1H), 4.61 (dt, J=47.4, 4.9 Hz, 2H), 4.08 (s, 2H), 3.82 (dt, J=26.0, 4.9 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH3:13])=[N:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=1.[C:14]([OH:18])(=O)[CH2:15]O>>[CH:9]([O:8][C:5]1[N:4]=[C:3]2[N:12]([CH3:13])[C:15]([CH2:14][OH:18])=[N:1][C:2]2=[CH:7][CH:6]=1)([CH3:11])[CH3:10]
Reactant: O=C(O)CO
Reactant: CNc1nc(OC(C)C)ccc1N
Product: CC(C)Oc1ccc2nc(CO)n(C)c2n1
Yield: 25 %

Procedure:
A procedure similar to that described in Preparation 43 was repeated, except that 1.90 g of 3-amino-6-isopropoxy-2-methylaminopyridine (prepared as described in Preparation 101), and 2.39 g of glycolic acid were used, and that the product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol, to give 0.58 g of the title compound, melting at 125-127° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[OH:15])=[CH:5][CH:4]=1>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][C:12]=3[C:13](=[O:16])[C:14]=2[O:15][CH2:13][C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2oc3ccc(NC(=O)OC(C)(C)C)cc3c(=O)c2O)cn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2oc3ccc(NC(=O)OC(C)(C)C)cc3c(=O)c2OCc2ccccc2)cn1
Yield: 74 %

Procedure:
Prepared analogously to Example 5d), starting from 2-(6-methoxypyridin-3-yl)-3-hydroxy-6-(N-tertbutoxycarbonylamino)-4H-1-benzopyran-4-one. Yield: 74%; TLC (9/1 Chloroform/Methanol): Rf 0.89, 1H-NMR (d6-DMSO): 9.78 (s broad, 1H), 8.81 (d, 1H), 8.31 (d, 1H), 8.25 (dd, 1H); 7.79 (dd, 1H); 7.68 (d, 1H); 7.30 (m, 5H), 6.97 (d, 1H); 5.16 (s, 2H), 3.94 (s, 3H), 1.52 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[CH3:11][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[CH2:31]Cl)[CH2:23][CH2:22]1)[CH3:13]>CN(C=O)C>[CH3:13][CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][C:28]2[CH:29]=[C:30]([CH2:31][N:3]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]3=[O:10])[CH:33]=[CH:34][CH:35]=2)[CH2:23][CH2:22]1)[CH3:11]
Reactant: O=C1CCCC(=O)N1
Reactant: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CCl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccccc1N1CCN(Cc2cccc(CN3C(=O)CCCC3=O)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of NaH (0.224g, 7.48 mmol) and DMF (10 mL) was treated slowly with 2,6-piperidinedione (0.846 g, 7.48 mmol) at room temperature. After the addition was complete, the mixture was cooled to 0° C. and a solution of 3-[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]benzyl chloride (2.46 g, 7.12 mmol) and DMF (10 mL) was added dropwise. The cooling bath was removed and the reaction was stirred at room temperature overnight. A small portion of water was added and the reaction was concentrated under vacuum. The residue was partitioned between CH2Cl2 /water and the organic layer was separated, dried, and evaporated to give 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidine-2,6-dione as an oil, 3.25 g. This material was dissolved in i-PrOH (13 mL) and treated with maleic acid (0.83 g, 7.15 mmol). Trituration with ether, filtration, and drying afforded 1-[[3-[[1-[2-(1-methylethoxy)phenyl]-4-piperazinyl]methyl]phenyl]methyl]-piperidine-2,6-dione (Z)-2-butenedioate (1:1) as a white solid (2.73 g, 70%), m.p. 103°-105° C. 1H NMR and mass spectral analysis supported the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:27][CH:26]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(-n2cccn2)cc1

Procedure:
The title compound was prepared by the method of Preparation 1c using (3-amino-4-chlorophenoxy)acetic acid methyl ester and 3-oxo-2-(4-pyrazol-1-ylbenzyl)pentanoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][CH2:7][CH:8](O)[C:9]1[C:14]([F:15])=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[CH:10]=1.S(=O)(=O)(O)O.C([O-])(=O)C.[Na+]>FC(F)(F)C(O)=O>[F:15][C:14]1[C:9]([CH:8]2[C:21]3[C:4](=[C:3]([O:2][CH3:1])[C:24]([O:25][CH3:26])=[CH:23][CH:22]=3)[CH2:5][NH:6][CH2:7]2)=[CH:10][C:11]([O:18][CH3:19])=[C:12]([O:16][CH3:17])[CH:13]=1
Reactant: COc1cc(F)c(C(O)CNCc2cccc(OC)c2OC)cc1OC
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(F)c(C2CNCc3c2ccc(OC)c3OC)cc1OC
Yield: 98.9 %

Procedure:
α-[[(2,3-dimethoxybenzyl)amino]methyl]-6-fluoro-3,4-dimethoxybenzyl alcohol (1.0 g) was dissolved in 7 ml of trifluoroacetic acid, and after adding thereto under ice cooling, conc. sulfuric acid (0.25 ml), the mixture was stirred for 40 minutes. 0.72 g of sodium acetate was added to the reaction mixture, and the mixture was concentrated. To the residue was added chloroform and water, and the mixture was basified by addition of conc. aqueous ammonia under ice cooling. After separating procedure, the chloroform layer was collected, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was distilled off, 0.94 g of 4-(6-fluoro-3,4-dimethoxyphenyl)-7,8-dimethoxy-1,2,3,4-tetrahydroisoquinoline was obtained as a syrupy matter.
Reaction SMILES: [CH:1]([C:3]1[C:4]([CH3:23])=[C:5]([O:13][CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C:6]([CH3:12])=[N:7][C:8]=1[CH2:9][CH2:10][CH3:11])=O.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[CH3:1][CH3:3].[C:18]([C:17]1[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=1)[CH2:14][O:13][C:5]1[C:4]([CH3:23])=[C:3]([CH2:1][NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=2)[C:8]([CH2:9][CH2:10][CH3:11])=[N:7][C:6]=1[CH3:12])#[N:19]
Reactant: CCCc1nc(C)c(OCc2cccc(C#N)c2)c(C)c1C=O
Reactant: N#Cc1ccc(N)cc1
Product: CC
Product: CCCc1nc(C)c(OCc2cccc(C#N)c2)c(C)c1CNc1ccc(C#N)cc1
Yield: 67.5 %

Procedure:
The reductive amination of 3-(5-formyl-2,4-dimethyl-6-propyl-pyridin-3-yloxymethyl)-benzonitrile (179) (675 mg, 2.18 mmol) and 4-aminobenzonitrile (516 mg, 4.4 mmol), was carried out as described in Example 21, gave 4-{[5-(3-cyano-benzyloxy)-4,6-dimethyl-2-propyl-pyridin-3-ylmethyl]-amino}-benzonitrile (180) (324 mg, 36% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32]Cl)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([CH:30]=[CH:31][CH2:32][N:14]2[C:13](=[O:16])[CH:12]=[C:11]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(-c2cc(=O)[nH]nc2-c2ccc(OC)c(F)c2)cc1
Reactant: ClCC=Cc1ccc(Cl)cc1
Product: COc1ccc(-c2cc(=O)n(CC=Cc3ccc(Cl)cc3)nc2-c2ccc(OC)c(F)c2)cc1
Yield: 72.5 %

Procedure:
Using 6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-one and 4-chlorocinnamyl chloride as starting materials, the procedures of Example 12 were repeated likewise, whereby the title compound was obtained in a yield of 72.5%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[CH2:19][CH:20]=[CH2:21].Cl(O)(=O)(=O)=O.[I:27]N1C(=O)CCC1=O.S([O-])([O-])=O.[Na+].[Na+]>O.O1CCCC1>[I:27][CH2:21][CH:20]1[O:18][C:4]2[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[C:11]([C:2](=[O:1])[C:3]=2[CH2:19]1)=[CH:10][CH:9]=[CH:8][N:7]=3
Reactant: C=CCc1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2c(n(-c3ccccc3)c3ncccc13)OC(CI)C2

Procedure:
To a solution of 4.0 g. (0.014 moles) of 4-hydroxy-1-phenyl-3-(2-propenyl)-1,8-naphthyridin-2(1H)-one in 380 ml. of tetrahydrofuran, there is added, dropwise, with stirring at 3°-5° C., 4.0 g. of 70% perchloric acid in 11.5 ml. of water, followed by the slow addition of 10.2 g. of N-iodo-succinimide over a period of 45 minutes. The reaction is stirred at room temperature for three hours, treated with a saturated solution of sodium sulfite, and extracted with 2×250 ml. of ether. The organic layer is dried over magnesium sulfate, filtered and concentrated to a solid residue. The crude products are separated on a 60G silica gel column with methanol:chloroform (5:95). The desired fraction is recrystallized from ethyl acetate to yield the title compound, m.p. 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH3:18])[CH2:10][O:11]C2CCCCO2)[C:3]=1[F:19].O.C(O)(=O)C>C1COCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH3:18])[CH2:10][OH:11])[C:3]=1[F:19]
Reactant: CC(COC1CCCCO1)c1ncc(F)c(Cl)c1F
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(CO)c1ncc(F)c(Cl)c1F
Temperature: 45 °C

Procedure:
The product of Step 1 is dissolved in 200 mL of 2:1 THF:water and to this solution is added 6 mL of acetic acid. The reaction mixture is heated at 45° C. for approximately 5 hours. The THF is removed under reduced pressure and the aqueous reaction mixture is adjusted to a pH in the range of 8 to 9 with 10% sodium carbonate and is then extracted with methylene chloride. The organic layer is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]2[C:14](=[C:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:6][CH:5]=1.C=O.[CH2:22](N(CC)CC)C.[H][H]>C(O)C>[CH3:22][N:10]1[CH2:11][CH2:12][CH2:13][C:14](=[C:15]([CH3:17])[CH3:16])[CH:9]1[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: [H][H]
Reactant: COc1ccc(CC2NCCCC2=C(C)C)cc1
Agent: C=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(CC2C(=C(C)C)CCCN2C)cc1
Temperature: 25 °C

Procedure:
A mixture of 2.8 g. 2-(p-methoxybenzyl)-3-isopropylidenepiperidine hydrochloride, 0.8 ml. of 35% aqueous formaldehyde solution, 1.4 ml. of triethylamine, and ethanol to a total volume of 50 ml. was shaken at room temperature under 50 p.s.i. of hydrogen. The theoretical quantity of hydrogen was consumed in 1 hour. The reaction mixture was filtered and the residue thus collected was rinsed with a small amount of ethanol. Th filtrate and rinse were combined and evaporated to dryness under reduced pressure and the residue was partitioned between dilute ammonium hydroxide and diethyl ether. The ether layer was washed with water, dried, and filtered, and the filtrate evaporated to dryness under reduced pressure to give 1.9 g of 1-methyl-2-(p-methoxybenzyl)-3-isopropylidenepiperidine as a syrup. This was taken up in 50 ml. of diethyl ether and treated with a slight excess of ethereal hydrogen chloride to precipitate a gum. Addition of 5 ml. of isopropyl alcohol and trituration caused crystallization. Recrystallization from 5 ml. of isopropyl alcohol and 50 ml. of diethyl ether afforded the pure compound which melted at 179°-183°C; ir (KBr) 1670 cm-1 (tetrasubstituted double bond); nmr (of base, CDCl3): 147 (s,3); 93 (s,3); 63 (d3, J=1-2 cps).