Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:19](Cl)([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20].C(N(C(C)C)CC)(C)C>O1CCOCC1.O>[C:19]([N:5]1[CH2:4][CH2:3][N:2]([C:8]2[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([O:21][CH2:22][CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30]2[C:35]1=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:20]
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(O)c1ccc(N2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Piperazin-1-yl-benzoic acid hydrochlorid (10.5 mmol) is dissolved in 15 ml Dioxan and 11.6 ml NaOH (2N) and cooled to 0° C. Simultaneously, FMOC-chloride (11.6 mmol) in dioxan (5 ml) and diisopropyl-ethylamine (11.6 mmol) in dioxan (5 ml) are added dropwise over 20 minutes at 0° C. and the mixture is stirred for 15 minutes and is then allowed to warm up to rt and is stirred over night. The mixture is diluted with water (50 ml) and extracted 2 times with diethylether. The water phase is acidified with aqueous HCl (4N) at 0-4° C. and the solid material formed is filtered off, washed with water and dried (vacuum). A white powder with Rf=0.2 (CH2Cl2/MeOH =95:5) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][C:3]=1[F:21].[CH3:22][N:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30]([C:33](O)=[O:34])[CH:31]=[N:32][C:24]1=2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:33]([C:30]3[CH:31]=[N:32][C:24]4[N:23]([CH3:22])[CH2:28][CH2:27][O:26][C:25]=4[CH:29]=3)=[O:34])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:4][C:3]=1[F:21]
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Reactant: CN1CCOc2cc(C(=O)O)cnc21
Product: CN1CCOc2cc(C(=O)Nc3cnc(OCC(F)(F)F)c(-c4ccc(Cl)c(F)c4)c3)cnc21

Procedure:
The title compound was synthesized in analogy to Example 42 g, using 5-(4-chloro-3-fluoro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylamine (example 81 a) and 3,4-dihydro-4-methyl-2H-pyrido[3,2-b]-1,4-oxazine-7-carboxylic acid (CAN 915707-58-3) as starting materials; MS (EI) 497.2(M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:16]=[CH:17][CH:18]=1>[OH-].[K+]>[CH2:1]([C:4]1([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[C:8](=[O:9])[CH2:7][CH2:6][C:5]1=[O:10])[CH2:2][CH3:3]
Reactant: C=CC(=O)CCCc1cccc(OC)c1
Reactant: CCCC1C(=O)CCC1=O
Agent: [K+]
Agent: [OH-]
Product: CCCC1(CCC(=O)CCCc2cccc(OC)c2)C(=O)CCC1=O
Yield: 79.6 %

Procedure:
Condense 2-propyl-1,3-cyclopentanedione (13.1 g) in 0.12% methanolic potassium hydroxide solution (90 cc) with 6-m-methoxyphenylhex-1-en-3-one (19.0 g), to obtain crude 2-propyl-2-(6-m-methoxyphenyl-3-oxohexyl)cyclopentane-1,3-dione (25.5 g). Submit this Michael condensation product (23.4 g) to double cyclodehydration; distil the product at 200°/10-4 mm. and crystallize the distillate from ethanol, to obtain the tetracyclic diene ketone, m.p. 82°-84°; ultraviolet absorption peak at 310 mμ (ε24,700).
Reaction SMILES: [CH2:1]([N+](CCCC)(CCCC)CCCC)CCC.[C:18]([O:23]CCN(C)C)(=[O:22])[C:19]([CH3:21])=C.[C:29]([O:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:33])[C:30]([CH3:32])=[CH2:31].C(O[Si](C)(C)C)(=O)C(C)=C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO>[C:29]([O:34][CH2:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)(=[O:33])[C:30]([CH3:32])=[CH2:31].[CH3:1]/[CH:21]=[CH:19]/[C:18]([OH:23])=[O:22]
Reactant: C=C(C)C(=O)OCCN(C)C
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C=C(C)C(=O)OCCc1ccccc1
Agent: C=C(C)C(=O)O[Si](C)(C)C
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C=C/C(=O)O
Reaction time: 9 h

Procedure:
To a solution of 4.86 g (5.52 mL, 21.0 mmol) of 1-(2-dimethylamino-ethoxy)-1-trimethyl-siloxy-2-methyl-1-propene, 0.1 mL of tetrabutylammonium biacetate hexahydrate (0.04M in THF) in 30 mL of THF was added a mixture of 6.6 g (7.1 mL, 42 mmol) of 2-dimethylaminoethyl methacrylate (purified by distillation and passage over a column of basic alumina under argon), and 31.6 g (31.6 mL, 168 mmol) of 2-phenylethyl methacrylate (purified by passage over a column of basic alumina under argon) from an addition funnel. The temperature of the reaction mixture rose to 62° C. during the course of the addition, and an ice bath was used to moderate the temperature rise. When, following the conclusion of the addition, the temperature was 26° C., the dropwise addition of 43.2 g (49 mL, 273 mmol) of trimethylsilyl methacrylate was begun. During the course of the addition the temperature of the reaction mixture rose to 45° C. while a total of 1.25 mL of tetrabutylammonium biacetate hexahydrate (0.04M in THF) was added in 9 additions. Analysis of an aliquot of the solution by 1H NMR showed that there was no residual monomer present. After addition of 55 mL of THF, 56 mL of methanol, and 0.086 g (2.7 mmol) of tetrabutylammonium fluoride trihydrate the solution was refluxed for 9 hr. Then 50 mL of THF was added, and refluxing was continued for an additional 9 hr. The solution was evaporated under reduced pressure with a rotary evaporator. The solid residue was dried in a vacuum oven at 80° C. for 8 hr to give 57 g of poly ω-2-β-dimethylaminoethyl isobutyrate(2-dimethylaminoethyl methacrylate [9 mol %]-co-2-phenylethyl methacrylate [35 mol %]-b-methacrylic acid [56 mol %]) 1H NMR analysis of the polymer showed that virtually no trimethylsilyl groups remained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](Cl)=[N:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=O)(C)(C)C>>[CH2:1]([N:8]1[C:12]2[C:13]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[N:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:18][C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#Cc1ccccc1Cn1c(=O)n(Cc2ccccc2)c2c(Cl)nccc21
Product: N#Cc1ccccc1Cn1c(=O)n(Cc2ccccc2)c2c(N3CCNCC3)nccc21

Procedure:
2-(3-benzyl-4-chloro-2-oxo-2,3-dihydroimidazo[4.5-c]pyridin-1-ylmethyl)benzonitrile (0.364 g) and piperazine-1-carboxylic acid t-butyl ester (0.543 g) were heated at 170° C. for 12 hours. The residue was cooled, and then purified by silica gel chromatography using amine-treated silica.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1.CO.[CH3:23][NH2:24].O>O1CCCC1>[CH3:23][NH:24][C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH2:18][CH2:19][F:20])[CH:14]=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: FCCOc1ccc2cc(-c3ccnc(Cl)n3)sc2c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nccc(-c2cc3ccc(OCCF)cc3s2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.4 %

Procedure:
2-(2-Chloropyrimidine-4-yl)-6-(2-fluoroethoxy)benzothiophene (105b, 80 mg, 0.26 mmol) obtained in Preparation Example 20 was dissolved in anhydrous tetrahydrofuran (4 mL). A 2.0 M methylamine methanol solution (NH2Me in MeOH, 0.26 mL, 0.52 mmol) was added to the reaction mixture and stirred at room temperature for 3 days. To the reaction mixture was added water and organic compounds were extracted with ethyl acetate and evaporated after a treatment with sodium sulfate. Column chromatography was performed to give the target compound 2-[2-(N-monomethylamino)pyrimidine-4-yl]-6-(2-fluoroethoxy)benzothiophene (1-35, 50 mg, 63%) as a yellow solid.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][C:6]([C:24]([NH2:26])=[O:25])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.[NH2:47][C@@H:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49]1>CN1C(=O)CCC1.CCOC(C)=O>[C:24]([C:6]1[N:5]=[N:4][C:3]([NH:47][C@@H:48]2[CH2:53][CH2:52][CH2:51][N:50]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:49]2)=[N:8][C:7]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1)(=[O:25])[NH2:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: CSc1nnc(C(N)=O)c(Nc2ccc(C(=O)N3CCOCC3)cc2)n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2nnc(C(N)=O)c(Nc3ccc(C(=O)N4CCOCC4)cc3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 3-(methylthio)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (170 mg, 0.46 mmol) in NMP (20 mL) was added mCPBA (77% strength, 310 mg, 1.38 mmol). The mixture was stirred at RT for 1 h to yield a mixture of corresponding sulfone and sulfoxide. To the mixture was then added DIEA (0.40 mL, 2.30 mmol) and (R)-tert-butyl 3-aminopiperidine-1-carboxylate (184 mg, 0.92 mmol). The mixture was heated at 90° C. for 90 m. The mixture was cooled, diluted with 300 mL EtOAc, washed with 1N NaOH and brine, dried, and concentrated in vacuo. The residue was subjected to flash column chromatography with 0 to 6% MeOH in DCM to yield the title compound (74) (210 mg, 87% yield). MS found C25H34N8O5 as (M+H)+ 527.2, (M−H)− 525.3. UV: λ=252, 267, 283 nm.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:10]([CH3:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:15][C:10]1[C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccnc1C

Procedure:
Acetic Acid Anhydride (17.9 mmol; 1.7 mL) was added to 3-Amino-2-picoline (17.0 mmol; 1.8 g) in dichloromethane (10 mL) and diisopropylethylamine (17.9 mmol; 3.1 mL) at 25° C. under argon. The reaction aged 30 min at 25° C. then was diluted with dichloromethane and extracted with water and brine. The aqueous layer was extracted with dichloromethane and ether then the combined organics were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting yellow oil was purified by chromatography (0% to 66% ethyl acetate in hexane) to afford the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCc1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 80 %

Procedure:
A solution of 2-(4-trifluoromethylphenyl)-ethanol (570 mg, 3.0 mmol) in pyridine (6 mL) was stirred on an ice/acetone bath and treated with p-toluenesulfonyl chloride (630 mg, 3.3 mmol). The cooling bath was replaced with an ice/water bath and the mixture was stirred for 3.5 hours. Ice-cold water (12 mL) was added slowly, and the mixture was extracted three times with chloroform. The combined organic phases were washed with water, then with cold 1.0 N aqueous sulfuric acid until the wash phase was acidic. The organic phase was dried over sodium sulfate and concentrated to provide a white solid (826 mg) which contained about 10% by weight of residual alcohol. This was used without further purification. 1H NMR (300 MHz, CDCl3) for toluenesulfonate: δ7.65 (d, J=8 Hz, 2H), 7.50 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H), 7.23 (d, J=8 Hz, 2H), 4.26 (t, J=7 Hz, 2H), 3.02 (t, J=7 Hz, 2H), 2.44 (s, 3H).
Reaction SMILES: C1(C)C=C(C)C=C(C)C=1S(O[NH2:13])(=O)=O.[C:15]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([OH:43])=[O:42])[N:39]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:15]([N:34]=[C:35]1[N:39]([NH2:13])[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([OH:43])=[O:42])=[CH:37][S:36]1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: ClCCl
Product: CON=C(C(=O)O)c1csc(=NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1N

Procedure:
O-mesitylenesulfonylhydroxylamine (1.3 g.) was added at room temperature to a stirred suspension of 2-(2-tritylamino-4-thiazolyl)-2-methoxyimino acetic acid (2.15 g) in methylene chloride (40 ml), thus giving in a few minutes the complete dissolution of the reaction mixture. Stirring was maintained for 18 hours, during which time the mesitylenesulfonic salt of the title compound slowly separates as a white solid. The product was filtered and washed with ethyl ether, thus giving 2.98 g (92%) of 2-(2-tritylimino-3-amino-4-thiazolinyl)-2-methoxyimino acetic acid, mesitylene sulfonate, m.p.=161°-163° dec.
Reaction SMILES: [NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:20])=[O:19])[C:15]([Br:17])=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.BrN1C(=O)CCC1=O.C(O)(=O)C>C(OC(=O)C(C)(C)C)(=O)C(C)(C)C>[NH2:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])(=[O:19])=[O:20])[C:15]([Br:17])=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCN(CC)S(=O)(=O)c1cc2c(cc1Br)CCc1nc(N)[nH]c(=O)c1-2
Agent: CC(C)(C)C(=O)OC(=O)C(C)(C)C
Agent: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCN(CC)S(=O)(=O)c1cc2c(ccc3nc(N)[nH]c(=O)c32)cc1Br
Temperature: 25 °C
Yield: 33.2 %

Procedure:
3-Amino-8-bromo-N,N,-diethyl-5,6-dihydrobenzo[f]quinazolin-1(2H)-one-9-sulfonamide (0.165 g, 0.39 mmole) was suspended in pivalic anhydride (5 ml) (Aldrich) and heated under nitrogen until dissolved. The solution was heated under reflux for 10 minutes, cooled, and the pivalic anhydride removed in vacuo. The dried solid was dissolved in benzene (20 ml), pyridine (0.05 ml) added, and the solution heated to boiling under nitrogen. N-Bromosuccinimide (0.079, 0.47 mmole) added, and the mixture refluxed for an additional 6 hours. The reaction mixture was cooled to room temperature, solvent removed in vacuo, and the solid residue crystallized from methanol. The pivalamide (0.105 g) was dissolved in methanol (2 ml), 1N NaOH(4 ml) added, and the solution heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was neutralized with dilute acetic acid, the crystals collected by filtration and suspended in methanol. The collected crystals were dried in vacuo to give 3-amino-8-bromo-N,N-diethyl-1,2-dihydro-1-oxobenzo[f]quinazolin-9-sulfonamide (0.055 g, 33%). Mp>250° C. 1H NMR (DMSO-d6, 200 MHz) δ: 1.10 (t, J=7 Hz, 6H, ethyl CH3), 3.38 (q, J=7 Hz, 4H, ethyl CH2), 6.78 (br s, 2H, NH2), 7.47 (d, J=9 Hz, 1H, Ar), 8.09 (d, J=9 Hz, 1H, Ar), 8.40 (s, 1H, Ar), 10.30 (s, 1H, Ar), 11.32 (br s 1H, NH). Anal Calculated for C16H17BrN4O3S: C,45.19; H,4.03; Br,18.79; N,13.17; S,7.54. Found: C,45.10; H,4.03; Br,18.74; N,13.07; S,7.56.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([CH2:20]C)[CH:17]=[C:16]([CH2:22]C)[CH:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>O.CCO.[Pd]>[CH3:20][C:18]1[CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:15]=[C:16]([CH3:22])[CH:17]=1
Reactant: CCc1cc(CC)cc(C2=CCN(Cc3ccccc3)CC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: O=CO
Solvent: O
Product: Cc1cc(C)cc(C2CCNCC2)c1
Reaction time: 6 h
Yield: 83.3 %

Procedure:
1.24 g of 10% Pd on activated carbon were suspended in 15 mL of water, then a solution of 4.4 g (15.86 mmol) of 1-benzyl-4-(3,5-diethylphenyl)-1,2,3,6-tetrahydropyridine in 60 mL of EtOH was added followed by 1 mL of formic acid The resulting mixture was hydrogenated at 45 p.s.i. in a Parr apparatus for 6 h, then the catalyst was filtered off and the solvent was removed in vacuo. The resulting residue was taken up in water, basified with conc. NH4OH solution and extracted with CH2Cl2. The organic phase was dried and the solvent was removed in vacuo, yielding 2.5 g of the title compound, which was used without further purification.
Reaction SMILES: OC1C=C([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])C=CC=1.Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].BrCCC[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]1[O:42]CCO1>>[C:11]([O:10][C:9]([NH:8][CH:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:36]1[CH:37]=[C:38]([CH:33]=[CH:34][CH:35]=1)[O:42][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)c1cccc(O)c1
Reactant: BrCCCCCCCCC1OCCO1
Product: COC(=O)COc1cccc(C(NC(=O)OC(C)(C)C)c2ccccc2)c1

Procedure:
The title compound was prepared as described in Example 1 Step 1 with tert-butyl (3-hydroxyphenyl)(phenyl)methylcarbamate and methyl bromoacetate replacing 3-hydroxybenzophenone and 2-(8-bromooctyl)-1,3-dioxolane, respectively
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([OH:17])=O)=[CH:6]2.C(N(CC)CC)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:42][N:43]1[CH2:47][CH2:46][NH:45][C:44]1=[O:48]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][C:7]([C:15]([NH:42][N:43]1[CH2:47][CH2:46][NH:45][C:44]1=[O:48])=[O:17])=[CH:6]2
Reactant: NN1CCNC1=O
Reactant: COc1cc2cnc(C(=O)O)cc2cc1OC
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2cnc(C(=O)NN3CCNC3=O)cc2cc1OC
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 6,7-dimethoxy-3-isoquinolinecarboxylic acid (6.99 g, 30.0 mmol) in 300 ml of N,N-dimethylformamide were added triethylamine (12.14 g, 120.0 mmol) and diphenyl chlorophosphate (80.6 g, 30.0 mmol) at 0° C. After stirring for 4 hours at 0° C., N-amino-2-oxoimidazolidine (3.03 g, 30.0 mmol) was added, and the mixture was stirred at 0° C. overnight. Ammonium salts (2.0 g) were filtered off, and the filtrate was evaporated in vacuo. The residue was triturated with a 1:1 mixture of water and ethyl acetate. The solid was filtered off and triturated twice with water at pH 8 for 3 hours. The remaining solid was filtered off, washed with water and dried in vacuo. Yield: 4.30 g; melting point 220° C. (dec.).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1>>[OH:28][C:22]1([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:27][CH2:26][CH2:25][N:24]([C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:12])[CH2:23]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc4ccccc4c3)C2)c1

Procedure:
The compound of Example 28 was prepared according to the general preparation protocol A from naphthalene-2-carbonyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl.N1C=CC=CC=1.[C:26](Cl)(=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30]>O>[C:26]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:31])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCC(=O)Cl
Reactant: CCCCCOc1cc(C(=O)O)ccc1N
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCCCCOc1cc(C(=O)O)ccc1NC(=O)CCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
4-Amino-3-pentyloxybenzoic acid (200 mg, 0.90 mmol), methylene chloride (5 ml) and pyridine (0.081 ml, 1.0 mmol) were mixed, and valeryl chloride (0.11 ml, 0.90 mmol) was added to this solution. The mixture was stirred at room temperature for 0.5 hour. Water was added to the reaction mixture, and the aqueous layer was extracted 3 times with ethyl acetate (5 ml). The organic layers were combined, washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained crude crystals were washed with hexane to give 4-pentanoylamino-3-pentyloxybenzoic acid (109.5 mg, 400%) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][O:5][C:6](=[O:17])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16].CC(CCC1C=CC=CC=1)CCO>>[CH3:1][CH:2]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:3][CH2:4][O:5][C:6](=[O:17])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[OH:16]
Reactant: Cc1ccc(O)c(C=CC(=O)OCCC(C)CCc2ccccc2)c1
Agent: CC(CCO)CCc1ccccc1
Product: Cc1ccc(O)c(/C=C/C(=O)OCCC(C)CCc2ccccc2)c1

Procedure:
According to the same procedure, 3-(2-hydroxy-5-methyl-phenyl)-acrylic acid 3-methyl-5-phenyl-pentyl ester was prepared from 3-(2-hydroxy-.5-methyl-phenyl)-acrylic acid ethyl ester, 3-methyl-5-phenyl-pentanol and tetraisopropyl-o-titanate.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH2:6][NH:7][CH:8]1[CH2:10][CH2:9]1.I[CH3:16].Cl>O1CCCC1>[Br:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH2:6][NH:7][CH2:8][CH:10]1[CH2:9][CH2:16]1
Reactant: Brc1ccccc1CNC1CC1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccccc1CNCC1CC1
Temperature: 0 °C

Procedure:
53 mg of sodium hydride in 3 ml of tetrahydrofuran are added to 300 mg of (2-bromobenzyl)cyclopropylamine in 2 ml of tetrahydrofuran with ice-cooling. 207 μl of iodomethane are subsequently added, and the mixture is heated at 600 for 1 h. The mixture is allowed to cool and poured onto 20 g of ice and 5 ml of 1N hydrochloric acid, washed 4 times with 10 ml of ethyl acetate each time, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1.Cl>CN(C=O)C.N1CCCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[O:12][C:21]([C:18]3[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[CH:22][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(O)c(I)c1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2oc(-c3ccc(OC)cc3)cc2c1
Temperature: 6 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
A mixture of Methyl 3-Iodo-4-hydroxybenzoate (0.7 g, 2.5 mmol), 4-Methoxyphenylacetylene (0.33 g, 2.5 mmol), Pd(Cl)2(PPh3)2 (0.05 g) and Cul (0.03 g) in DMF/Piperidine (20 ml) was heated at 6° C. After 2 hr, the reaction was cooled and poured into 2N HCl. The aqueous layer was extracted with EtOAc and then separated, dried, concentrated to give a solid. The solid was triturated with MeOH, filtered to give 142 (0.5 g, 71%): Mp=157–159° C.; 1H NMR (CDCl3) δ 8.28 (d, 1 H, J=1.3 Hz), 7.97 (dd, 1 H, J=8.5 Hz, 1.7 Hz), 7.82–7.79 (m, 2 H), 7.51 (d, 1 H, 8.5 Hz), 6.99 (d, 2 H, J=8.3 Hz), 6.93 (d, 1 H, J=9 Hz), 3.94 (s, 3 H), 3.87 (s, 3 H); MS 283 (M+H)+