Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([CH3:27])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([O:28][CH3:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:30]([NH2:33])([CH3:32])[CH3:31]>C(#N)C.O>[CH:30]([NH:33][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([O:28][CH3:29])[CH:11]=2)=[O:22])=[C:16]([CH3:27])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:32])[CH3:31]
Reactant: CC(C)N
Reactant: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)Nc2c(C)cc3cn[nH]c3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 500 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazol-3-yl]-5-methyl-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 10 mL of 4:1 (v/v) mixture of acetonitrile/water is added 1.0 mL (12.2 mmol) of isopropylamine. The reaction mixture is stirred during 1 hour at ambient temperature and for 2.5 hours at 60° C. and then concentrated in vacuo. The residue is taken-up with brine and tert-butylmethylether. The phases are separated and the aqueous layer is washed with tert-butylmethylether. The combined organic layers are washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography (SiO2, hexanes/ethyl acetate 3:7) affords 118 mg (19% over two steps) of the product as white solid; LC/MS:468/470 (M+H)+, m.p.: 148-151° C.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[F:19])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][C:21]([F:20])([F:31])[F:32])=[CH:24][CH:25]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OC
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: COc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
5-(2-Fluoro-6-methoxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one was prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-fluoro-6-methoxyphenyl)-2-methylbutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by FC (heptane/AcOEt=1/1) afforded the compound. LC-MS (conditions A): tR=0.93 min.; [M+H]+: 398.00 g/mol.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=1)[CH2:2]2.C(=O)([O-])O.[Na+].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl.CCOC(C)=O>[C:31]1([O:30][C:28](=[O:29])[NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([N:3]4[CH2:4][CH:5]5[O:8][CH:1]([CH2:7][CH2:6]5)[CH2:2]4)[N:14]=3)=[CH:16][CH:17]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(-c2ccnc(N3CC4CCC(C3)O4)n2)cc1)Oc1ccccc1

Procedure:
4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-4-yl)aniline (intermediate 26) (471 mg, 1.51 mmol) was stirred with sodium hydrogen carbonate (190 mg, 2.26 mmol) and phenyl chloroformate (285 μl, 2.26 mmol) in DCM (5 ml) at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with brine and the organics were concentrated in vacuo. The resulting yellow solid was purified by flash chromatography (0-100% EtOAc:Petroleum Ether 40-60) to afford the title compound. (60 mg, 10%)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[CH2:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.C[Si](C)(C)[O:15][C:16]([CH:18]=[CH2:19])=[CH2:17].B(F)(F)F.CCOCC>ClCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:19][CH2:18][C:16](=[O:15])[CH2:17][CH2:12]3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: C=C1Cc2ccc(Br)cc2C1=O
Reactant: C=CC(=C)O[Si](C)(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 48.1 %

Procedure:
In a flame dried 20 mL vial was placed 6-bromo-2-methylene-2,3-dihydro-1H-inden-1-one (98 mg, 0.441 mmol) and it was dissolved in dichloromethane (4.5 mL). To this solution was added 2-trimethylsilyloxy-1,3-butadiene (98 μL, 0.565 mmol) and the solution was cooled down to −78° C. After stirring for 5 minutes, BF3.OEt2 (27 mL, 0.219 mmol) was slowly added. After 5 minutes of the BF3.OEt2 addition, TLC indicated consumption of the dienophile. The reaction was quenched with MeOH (300 μL), allowed to stir for 5 minutes at −78° C. and then warmed up to room temperature. Once at room temperature, 2M HCl (7 mL) was added. The phases were separated and the aqueous phase was back-extracted with dichloromethane twice (5 mL/each). The combined organic phases were dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 6′-bromospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (62 mg, 0.212 mmol, 48% yield).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:20]([C:22]([C:37]#[N:38])=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[CH2:24]1)#[N:21].O>C(O)(=O)C>[CH2:1]([N:5]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[C:24]2[C:25](=[C:32]([C:35]#[N:36])[C:33]#[N:34])[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:23]2=[C:22]([C:20]#[N:21])[C:37]#[N:38])=[C:8]([O:14][CH3:15])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)c1ccc(C=O)c(OC)c1
Reactant: N#CC(C#N)=C1CC(=C(C#N)C#N)c2ccccc21
Solvent: CC(=O)O
Solvent: O
Product: CCCCN(CCCC)c1ccc(C=C2C(=C(C#N)C#N)c3ccccc3C2=C(C#N)C#N)c(OC)c1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
In 10 ml of anhydrous acetic acid were dissolved 0.8 g (3.04 mmol) of 4-(dibutylamino)-2-methoxybenzaldehyde and 0.73 g (3.01 mmol) of 1,3-bis(dicyanomethylidene)indan. The mixture was stirred with heating at 80° C. for 2 hours. The reaction mixture was poured into 200 ml of water and the precipitate was separated by filtration, washed with water, and dried. The crystal was purified by silica gel column chromatography and washed with methanol to give 1.27 g of a black crystal having a mp of 195-198° C. (yield: 86.4%).
Reaction SMILES: [N:1]([CH:4]([CH:10]([C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[N:1]([CH:4]([CH:10]([O:11][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)C(N=[N+]=[N-])C(O)c1cccnc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl

Procedure:
A procedure similar to that described in Preparation 49 was repeated, except that 3.90 g of ethyl 2-azido-3-(2-chloropyridin-3-yl)-3-hydroxypropionate (prepared as described in Preparation 76), 8.6 g of t-butyldimethylsilyl chloride, 10 g of imidazole and 80 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.6 g of the title compound having Rf=0.31 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](=[O:14])[CH2:8][C:9](OCC)=O)[CH2:3][CH2:2]1.[H-].[Na+].ClC1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[Cl:28])[CH:21]=[C:20]([C@@H:29]([NH:31][C:32]2[N:40]=[CH:39][N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH2:41][C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[CH3:30])[N:19]=1.O>C1COCC1>[Cl:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:9]([CH2:8][C:7]([N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)=[O:14])=[N:19][C:20]([C@@H:29]([NH:31][C:32]1[N:40]=[CH:39][N:38]=[C:37]3[C:33]=1[N:34]=[CH:35][N:36]3[CH2:41][C:42]1[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=1)[CH3:30])=[CH:21]2
Reactant: CCOC(=O)CC(=O)N1CCOCC1
Reactant: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(Cl)n4)ncnc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(CC(=O)N5CCOCC5)n4)ncnc32)cc1

Procedure:
To a mixture of ethyl 3-morpholino-3-oxopropanoate 33 (402 mg, 2 mmol, 1.0 eq) and NaH (144 mg, 3 mmol, 1.5 eq) in THF (3 mL) at RT, (S)—N-(1-(1,8-dichloroisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 1 (765 mg, 1.6 mmol, 0.8 eq) was added and the resulting mixture was stirred at reflux overnight. The reaction mixture was poured into water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product (S)-2-(8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinolin-1-yl)-1-morpholinoethanone 34.
Reaction SMILES: [CH3:1][CH:2]([CH:4]1[CH:9]=[C:8]2[CH2:10][CH2:11][CH:12]3[C:17]([C:19](O)=[O:20])([CH3:18])[CH2:16][CH2:15][CH2:14][C:13]3([CH3:22])[CH:7]2[CH2:6][CH2:5]1)[CH3:3].P(Cl)(Cl)[Cl:24].CN(C=O)C>C1COCC1>[CH3:18][C@:17]1([C:19]([Cl:24])=[O:20])[CH:12]2[C@@:13]([CH3:22])([CH:7]3[C:8]([CH:10]=[CH:11]2)=[CH:9][CH:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6]3)[CH2:14][CH2:15][CH2:16]1
Reactant: CC(C)C1C=C2CCC3C(C)(C(=O)O)CCCC3(C)C2CC1
Reactant: ClP(Cl)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)C1C=C2C=CC3[C@](C)(CCC[C@@]3(C)C(=O)Cl)C2CC1
Yield: 93.3 %

Procedure:
A mixture of dihydroabietic acid (1.0 eq. 9.95 mmol), phosphorous (III) chloride (1.1 eq. 10.95 mmol) and DMF (0.1 ml) is refluxed overnight in THF (20 ml). The reaction mass is filtered under suction and concentrated under vacuum to give 2.98 g (93%) yellow oil. The compound is used immediately for the next step without any purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.O1CCCC1.O1CCCC1.Cl[Zn][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1>Cl[Ni](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.O>[Cl:41][C:37]1[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=1)[CH2:34][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][S:17](=[O:21])(=[O:20])[CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Reactant: Cl[Zn]Cc1cccc(Cl)c1
Agent: Cl[Ni](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cnc(Cc2cccc(Cl)c2)nc1C(F)(F)F)N1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide (500 mg), dichlorobis(triphenylphosphine)nickel (II) (190 mg), tetrahydrofuran (10 mL) was added a 0.5 M chloro(3-chlorobenzyl)zinc tetrahydrofuran solution (3.2 mL), followed by stirring at room temperature for 6 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). To the obtained pale yellow solid were added 1,4-dioxane (10 mL) and 1-methylpiperazine (0.16 mL), followed by stirring at room temperature for 6 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate). The obtained white solid was washed with ethanol to obtain 4-{[2-(3-chlorobenzyl)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}thiomorpholine 1,1-dioxide (212 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: Nc1ccc(I)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(I)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
A solution of 2-chloro-4-iodoaniline (25 g, 96.66 mmol) in tetrahydrofuran (100 mL) was cooled to 0° C. and then treated with acetic anhydride (50.6 g, 500 mmol). The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was then concentrated in vacuo to remove tetrahydrofuran. The residue was crystallized from ether (50 mL) and hexanes (50 mL). The solids were collected and washed with hexanes to afford N-(2-chloro-4-iodo-phenyl)-acetamide (23.87 g, 84%) as a white crystalline solid: EI-HRMS m/e calcd for C8H7ClINO (M+) 295.1526, found 295.1532.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Br:7][C:8]1[N:9]([CH2:18][C:19]#[C:20][CH3:21])[C:10]2[C:15](=[O:16])[NH:14][N:13]=[CH:12][C:11]=2[N:17]=1.Cl[CH2:23][C:24]1[N:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>CN(C)C=O.O>[Br:7][C:8]1[N:9]([CH2:18][C:19]#[C:20][CH3:21])[C:10]2[C:15](=[O:16])[N:14]([CH2:23][C:24]3[N:33]=[C:32]([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[N:13]=[CH:12][C:11]=2[N:17]=1
Reactant: CC#CCn1c(Br)nc2cn[nH]c(=O)c21
Reactant: Cc1nc(CCl)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCn1c(Br)nc2cnn(Cc3nc(C)c4ccccc4n3)c(=O)c21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
489 mg (1.5 mmol) of caesium carbonate were added to a solution of 300 mg (1.12 mmol) of 2-bromo-3-(but-2-ynyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one and 260.1 mg (1.35 mmol) of 2-chloromethyl-4-methyl-quinazoline in 4.0 ml of dimethylformamide and this mixture was stirred for 2 hours under an argon atmosphere at 80° C. Then it was diluted with 10 ml of water and stirred for 30 minutes at ambient temperature. The crude product precipitated was suction filtered and purified by column chromatography (silica gel; eluant:petroleum ether with 20–50% ethyl acetate).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:13])(=[O:7])=[O:6]
Reactant: OCc1cccnc1
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(CO[C@@H](C(=O)OCc2cccnc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 50 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.28 mL of 3-pyridylmethanol (0.28 g, 2.5 mmol) in dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:1) to provide 0.30 g (50% yield) of the title compound (37a) as a colorless oil. Rf=0.34 (EtOAc/Hex=1:1). 1H NMR (400 MHz, CDCl3): δ=1.01 (s, 6H), 2.24-2.31 (m, 2H), 3.20-3.25 (m, 2H), 3.64-3.67 (m, 2H), 3.81 (s, 3H), 3.85 (s, 1H), 3.94 (d, J=9.6 Hz, 1H), 4.19 (d, J=8.8 Hz, 1H), 4.29 (d, J=10.8 Hz, 1H), 4.52 (d, J=11.2 Hz, 1H), 5.20 (s, 2H), 6.85 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.31-7.34 (m, 1H), 7.71-7.73 (m, 1H), 8.60-8.66 (m, 2H) ppm. MS (ESI) m/z 500.01 (M+H)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:23]([CH:31]1[O:35][C:34]2[CH:36]=[CH:37][C:38]([CH2:40]O)=[CH:39][C:33]=2[O:32]1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:40][C:38]3[CH:37]=[CH:36][C:34]4[O:35][CH:31]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[O:32][C:33]=4[CH:39]=3)=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCCCCCCCC1Oc2ccc(CO)cc2O1
Product: CCCCCCCCOc1cnc(-c2ccc(OCc3ccc4c(c3)OC(CCCCCCCC)O4)cc2)nc1

Procedure:
By Mitsunobu etherification of 4-(5-octyloxypyrimidin-2-yl)phenol using (2-octylbenzo[1,3]dioxol-5-yl)methanol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](S(Cl)(=O)=O)[CH:10]=2)[C:5]([Cl:16])=[CH:4][N:3]=1.ClN1C(=[O:23])CCC1=O.C1(=O)C2C(=CC=CC=2)C=CN1>CC#N>[Cl:16][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:23])[NH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: O=c1[nH]ccc2ccccc12
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccccc12
Temperature: 25 °C

Procedure:
1,4-Dichloro-7-isoquinolinesulphonyl chloride ##STR107## A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in MeCN (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid.
Reaction SMILES: Br[CH:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[OH:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH:17]=[C:16]([CH2:36][OH:37])[N:15]=1>>[OH:12][CH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][NH:23][CH:2]([CH3:11])[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH:17]=[C:16]([CH2:36][OH:37])[N:15]=1
Reactant: CC(Br)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCOc1cc(CO)nc(CO)c1
Product: CC(CC(=O)OC(C)(C)C)NCCOc1cc(CO)nc(CO)c1

Procedure:
Prepared as for Ex. 2, starting with tert-butyl 3-bromo-butyrate and N-[2-(2,6-bis-hydroxymethyl-pyridin-4-yloxy)-ethyl]-2-nitro-benzenesulfonamide:
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>>[ClH:1].[CH2:25]([N:12]1[CH2:13][CH2:14][C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:8][CH:7]=2)[C@H:10]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[CH2:11]1)[CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc(OC[C@@H]2CNCC[C@H]2c2ccc(F)cc2)cc1
Reactant: CCCCBr
Agent: Cl
Product: CCCCN1CC[C@@H](c2ccc(F)cc2)[C@H](COc2ccc(OC)cc2)C1

Procedure:
(-)-trans-1-butyl-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride M.p. 163°-165° C. was prepared exactly as described in Example 1 from (-)-trans-4-(4-fluorophenyl)-3-(4-methoxyphenoxymethyl)-piperidine hydrochloride and butyl bromide by refluxing for 120 hours.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (83 mg, 88%), MS (ISP) m/z=378.4 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(C(C)C)C(C)C)C1C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=[O:32])=[CH:26][CH:25]=1>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:32])=[CH:26][CH:25]=1
Reactant: CCCCCCCN
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: CC(C)N(Cc1ccccc1)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Cc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Heptan-1-amine (1 g, 8.679 mmol) was dissolved in dry THF under N2 and polymer supported N-benzyl-N,N-diisopropylamine (4.955 g, 26.038 mmol) was added. The mixture was stirred for 30 min and cooled to 0° C. and (4-chlorophenyl)acetyl chloride (1.969 g, 10.415 mmol) was added. The solution was stirred overnight at room temperature. The excess of (4-chlorophenyl)acetyl chloride was removed by filtering the mixture through an NH2 cartridge. The solvent was removed by evaporation. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4) and the solvent was removed by evaporation to give 1.045 g of 2-(4-chlorophenyl)-N-heptylacetamide (yield 45.0%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:20][Si:21]([CH2:24][CH2:25][O:26][CH2:27]Cl)([CH3:23])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH2:27][O:26][CH2:25][CH2:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ncc2cnc(Cl)cc21
Temperature: 30 °C
Reaction time: 20 h
Yield: 93 %

Procedure:
To a solution of 6-chloro-1H-pyrazolo[4,3-c]pyridine (2.00 g, 13.1 mmol) and DIPEA (3 mL) in DCM (10 mL) was added SEMCl (3 mL). The mixture was stirred at 30° C. for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using EtOAc/Petroleum Ether (10%˜60%) as eluting solvents to afford 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine as colorless oil (3.44 g, 93%). MS (ESI) m/z: 284 [M+H]+.