Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+].O>CC(=O)CC>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2

Procedure:
A mixture of 18.8 g (0.05 mole) of 2,7-bis(4-chlorobutyryl)fluorene, prepared in Example 10, 34.0 g (0.4 mole) of piperidine, 16.6 g (0.1 mole) of potassium iodide in 200 ml of butanone is stirred and refluxed for three days. The reaction mixture is poured into 1000 ml of water, and the solid which is precipitated is filtered and recrystallized twice from chlorform-acetone to give 2,7-bis(4-piperidinobutyryl)fluorene, M.P. 157°-159°C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:28])=[O:27].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCCl>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH:29][C:30](=[O:39])[O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:27])=[O:28])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: COC(CNS(=O)(=O)NC(=O)OCc1ccccc1)OC
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.5 %

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (68 mg, 0.20 mmol; from Step D) and benzyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (191 mg, 0.60 mmol, 3.0 equiv.) in 1,2-dichloroethane (3.0 mL) was cooled to 0° C. To this mixture was added trifluoroacetic acid (1.0 mL, 13.0 mmol) and triethylsilane (105 μL, 0.66 mmol, 3.3 equiv.) drop-wise. This reaction mixture was stirred at 0° C. for 2 h. HPLC indicated reaction completion. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. and the quenched reaction mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was then stirred in a mixture of heptane and diethyl ether overnight. The solids were collected by filtration, washed with heptane and dried in vacuum to give the desired product (125 mg, 99%) as a crude off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.05 (m, 1H), 7.87 (m, 1H), 7.68 (m, 1H), 7.56 (m, 1H), 7.32 (m, 5H), 6.54 (m, 1H), 5.07 (s, 2H), 3.29 (m, 2H), 3.09 (m, 2H); C20H17BrFN7O7S (MW 598.36), LCMS m/e 598/600 (M++H).
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.Cl>C1(C)C=CC=CC=1.C1COCC1>[NH2:1][C@@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:5]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1N=[N+]=[N-]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1N
Temperature: 25 °C

Procedure:
To a solution of tert-butyl (3R,4R)-4-azido-1-benzylpyrrolidin-3-ylcarbamate (7.0 g, 22.0 mmol) in 250 mL toluene, PPh3 6.0 g, 23.0 mmol) was added and the mixture was refluxed for 1 hour. The mixture was cooled down to room temperature, diluted with 250 mL THF, water (0.54 g, 30.0 mmol) was added and the mixture was refluxed for an additional 1 hour. 4N HCl was added, the aqueous acidic layer was separated, washed with CHCl3 and basified with aqueous NH3 to pH 9-10. The product was extracted with CHCl3, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 10% MeOH in CHCl3 giving the title mono-Boc protected diamine.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:10][C:11]1([N:24]2[CH:28]=[C:27]([C:29]3[CH:30]=[N:31][C:32]4[N:33]([C:35]([CH2:38][C:39]5[CH:40]=[C:41]6[C:46](=[CH:47][CH:48]=5)[N:45]=[CH:44][CH:43]=[CH:42]6)=[CH:36][N:37]=4)[N:34]=3)[CH:26]=[N:25]2)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)#[N:9]>C(Cl)Cl>[N:45]1[C:46]2[C:41](=[CH:40][C:39]([CH2:38][C:35]3[N:33]4[N:34]=[C:29]([C:27]5[CH:26]=[N:25][N:24]([C:11]6([CH2:10][C:8]#[N:9])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]6)[CH:28]=5)[CH:30]=[N:31][C:32]4=[N:37][CH:36]=3)=[CH:48][CH:47]=2)[CH:42]=[CH:43][CH:44]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CCC1(n2cc(-c3cnc4ncc(Cc5ccc6ncccc6c5)n4n3)cn2)CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic Acid (0.5 mL) was added to a solution of tert-butyl 4-(cyanomethyl)-4-{4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]-1H-pyrazol-1-yl}piperidine-1-carboxylate (0.015 g, 0.000027 mol) in methylene chloride (0.5 mL). The mixture was stirred at RT for 0.5 h. The volatiles were removed under reduced pressure to give the desired product as a TFA salt which was directly used in the next step without further purification. LCMS: (M+H)=450.5.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]>OS(O)(=O)=O>[CH:2]([C:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:5]([OH:6])[CH:4]=1)([CH3:15])[CH3:1]
Reactant: CC(C)C(=O)CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Product: CC(C)c1cc(O)nc2ccccc12
Yield: 57.8 %

Procedure:
A solution of 4-methyl-3-oxo-N-phenylpentanamide (3.70 g, 18.03 mmol) in 15 mL H2SO4 was reacted as outlined in Scheme 2 above to give 1.95 g (57%) of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=6.74 Hz, 6 H) 3.45 (quin, J=6.81 Hz, 1 H) 6.67 (s, 1 H) 7.15-7.32 (m, 1 H) 7.40-7.61 (m, 2 H) 7.79 (d, J=8.50 Hz, 1 H) 12.28 (br. s., 1 H).
Reaction SMILES: C[Al](C)C.Cl.[CH3:6][NH:7][O:8][CH3:9].[CH2:10]([C:13]1[N:14]([CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=1)[CH2:11][CH3:12]>C1(C)C=CC=CC=1.ClCCl>[CH3:9][O:8][N:7]([CH3:6])[C:29](=[O:30])[CH2:28][CH2:27][CH2:26][N:14]1[C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[CH:17][C:16]=2[N:25]=[C:13]1[CH2:10][CH2:11][CH3:12]
Reactant: CNOC
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(=O)N(C)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
A solution of trimethylaluminum in toluene (80 mL of a 2 M solution, 160 mmol) was added dropwise to a stirred suspension of N,O-dimethylhydroxylamine hydrochloride (15.6 g, 160 mmol) in dichloromethane (150 mL) at 0° C. After 15 minutes, the reaction flask was removed from bath and the solution stirred for 15 minutes at room temperature. The flask was then cooled in ice bath, and a solution of ethyl 4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyrate (34.7 g, 107 mmol) in dichloromethane (100 mL) was added rapidly dropwise. After 15 minutes, the ice bath was removed and the solution heated at reflux to cause considerable gas evolution. After 20 hours, a 10% solution of hydrochloric acid in water (15 mL) was added slowly, followed by a saturated solution of sodium bicarbonate in water (50 mL). The layers were separated, and the aqueous mixture was extracted with dichloromethane (2×50 mL). The combined organic solutions were washed successively with a 5% solution of sodium hydroxide in water (2×50 mL) and a saturated solution of sodium bicarbonate in water (1×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide N-methoxy-N-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyramide (35.9 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](C2CCOCC2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.[C:17]([OH:20])(=O)[CH3:18]>[Fe]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:6]2[CH2:18][CH2:17][O:20][CH2:4][CH2:5]2)=[C:6]([CH:7]=1)[NH2:8]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc(Br)ccc1C1CCOCC1
Agent: [Fe]
Product: Nc1cc(Br)ccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
A 3-neck flask was charged with 5-bromo-2-(tetrahydropyran-4-yl)nitrobenzene (see Working Example 18-1) (3.54 g, 11.8 mmol) and 10% aqueous acetic acid solution (65 mL), after which electrolytic iron (6.56 g, 118 mmol) was added and this was refluxed with stirring for 15 minutes. After this was allowed to cool to room temperature, the insoluble material was filtered off through Celite, and this same layer was further washed with 10% aqueous acetic acid solution (65 mL). The filtrate and the wash solutions were combined and then successively extracted with ethyl acetate (approx. 50 mL, 4 times), washed with distilled water (30 mL), and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and further drying under reduced pressure yielded the title compound (2.72 g, 85.4% yield) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[NH:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(OCC)(=O)C.[Cu](I)I.O1CCOCC1>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([N:19]2[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]2)[CH:7]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)n2)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 7.5 %

Procedure:
500 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 270 mg of ethyl 4-pyrazole carboxylate, 0.20 ml of trans-N,N′-dimethylcyclohexane-1,2-diamine, 780 mg of tripotassium phosphate and 100 mg of copper iodide were added in turn to 10 ml of degassed 1,4-dioxane, and the mixture was stirred at 100° C. for 6 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 51 mg of the objective compound as white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15].[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CCCc1ccc([N+](=O)[O-])cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCc1ccc([N+](=O)[O-])cc1F
Temperature: 21 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a solution of Methyl 4-(2-fluoro-4-nitrophenyl)butanoate (84) (43 mg, 0.18 mmol) in methanol (1 mL) and water (3 mL) was added sodium hydroxide (0.18 g, 4.50 mmol). The reaction mixture was stirred at 21° C. overnight. The reaction mixture was quenched with 1 N HCl solution and extracted with ethyl acetate (2×30 mL). The organic layer was dried over MgSO4, concentrated to give 4-(2-Fluoro-4-nitrophenyl)butanoic acid (82) (40 mg, 98%) and the residue was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[CH3:15][C:16]1[CH:17]=[C:18]([O:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1>C(Cl)(Cl)Cl>[CH3:15][C:16]1[CH:17]=[C:18]([O:22][C:23]([N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]2[NH:5][C:3]([O:2][CH3:1])=[O:4])=[NH:24])[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cccc(OC#N)c1
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1C(=N)Oc1cccc(C)c1
Temperature: 20 °C

Procedure:
To a suspension of 9.56 g. (0.05 mole) 2-(methoxycarbonylamino)-benzimidazole in 300 ml chloroform a solution of 7.19 g (0.054 mole) 3-methylphenyl cyanate in 20 ml chloroform is added in drops while stirring at 20°C. The reaction mixture is stirred for 5 hours at room temperature and then filtered. The clear filtrate is concentrated under vacuum until dry. The colorless crystalline residue is treated with ether.
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[N:8]2[CH3:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][N:18]=1>>[F:11][C:10]1[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([CH3:16])=[N:18][CH:19]=2)=[CH:3][CH:4]=[C:5]2[C:9]=1[N:8]([CH3:12])[C:7](=[O:13])[C:6]2([CH3:15])[CH3:14]
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)c(F)c21
Product: Cc1ccc(C(=O)Nc2ccc3c(c2F)N(C)C(=O)C3(C)C)cn1

Procedure:
Prepared in analogy to example 1b from 6-amino-7-fluoro-1,3,3-trimethylindolin-2-one (example 13d) and 6-methylnicotinic acid. The title compound was obtained as dark red foam.
Reaction SMILES: Cl.C[O:3][CH:4](OC)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH2:11])[N:6]=1.C([O-])([O-])=O.[Na+].[Na+].[BH4-].[Na+].[OH-].[Na+]>CO.C1COCC1.O.CCOC(C)=O>[NH2:11][C:7]1[N:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][N:8]=1
Reactant: COC(OC)c1ccnc(N)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1nccc(CO)n1
Reaction time: 16 h
Yield: 6.9 %

Procedure:
Aqueous HCl (2M, 207 mL, 828 mmol) was added to 4-(dimethoxymethyl)pyrimidin-2-amine (30) (WO 2007096764) (14.0 g, 83 mmol). The mixture was placed in a preheated oil bath at 48° C. for 16 hr. The mixture was cooled to RT and neutralized with solid Na2CO3 which produced a precipitate at pH 7. EtOAc (300 mL) was added, and the solid removed by filtration. After separation of the organic layer, the aqueous layer was extracted with 1% MeOH in THF (4×300 mL). The organics were combined, dried, filtered and evaporated to give crude aldehyde (ca. 4.0 g). This material was suspended in MeOH (100 mL), THF (100 mL) and water (100 mL) and treated with NaBH4 (1.565 g, 41.4 mmol). After stirring for 1 hr NaOH (1M, 20 mL) was added and the mixture was allowed to stand at RT for 48 hr. The solvents were evaporated to give a yellow solid which was partitioned between water (50 mL) and EtOAc (100 mL). The solid formed at the interface was removed by filtration and the aqueous layer was extracted with THF (3×300 mL), dried, filtered and evaporated to give a yellow solid. The material was suspended in THF (100 mL) and MeOH (50 mL) and absorbed onto silica gel (20 g) and subjected to column chromatography (80 g) eluting with 15% MeOH in DCM to give (2-aminopyrimidin-4-yl)MeOH (31) as an off-white solid (720 mg, 7%): m/z 126 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[CH3:37][C:38]([CH3:43])([CH3:42])[CH2:39][CH:40]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[CH3:37])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: CC(C)(C)CC=O
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCC(C)(C)C)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3-dimethyl-butyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3,3-dimethylbutyraldehyde instead of acetone and was obtained as a light brown oil. MS m/e: 608.2 [M]+.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].[C@@H:9]1([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([OH:22])[C:20]=3[N:19]=[CH:18]2)[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1>CN(C=O)C>[Si:5]([C@@:11]1([OH:12])[C@@H:13]([CH2:14][O:15][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])[O:16][C@@H:9]([N:17]2[C:26]3[N:25]=[CH:24][N:23]=[C:21]([OH:22])[C:20]=3[N:19]=[CH:18]2)[CH2:10]1)([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@]1(O)[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of TBSCl (1.91 g, 12.67 mmol) was added to a solution of 2′-deoxyinosine (1.00 g, 3.96 mmol) and imidiazole (1.73 g, 25.34 mmol) in anhydrous DMF (3 mL) at 0° C. under nitrogen atmosphere. The reaction mixture was gradually warmed to room temperature and stirred for 12 hours. The mixture was then concentrated in vacuo, dissolved in CH2Cl2 (100 mL), washed twice with water (50 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by silica gel chromatography to yield 3′,5′-O-bis-tert-butyldimethylsilyl-2′-deoxyinosine dA.n9 (1.58 g, 83%) as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9](=[O:23])[CH2:10][CH2:11][S:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)[CH:2]=1.[BH4-].[Na+].O>C(O)C>[C:13]1([S:12][CH2:11][CH2:10][CH:9]([OH:23])[CH2:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:14]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(CCSc1ccc2ccccc2c1)CCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(CCSc1cccc2ccccc12)CCc1cccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
1-(3-Pyridyl)-5-(2-naphthylthio)-3-pentanone (0.142 g) and sodium borohydride (0.025 g) were dissolved in ethanol (20 ml) and stirred for 15 hours at room temperature. Water was added to the reaction mixture, which was extracted with dichloromethane, the extracts dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:ethyl acetate (1:3) to give the title compound as a white solid (0.040 g).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([OH:12])[CH2:8][CH:9]([OH:11])[CH3:10].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>C(Cl)Cl>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:7][CH2:8][CH:9]([CH3:10])[OH:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CCO
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
Pyridine (9.0 ml, 111 mmol) was added to a solution of 1,3-butanediol (5.07 g, 56.3 mmol) in anhydrous methylene chloride (20 ml) at room temperature. After ice-cooling, p-toluenesulfonyl chloride (15.9 g, 83.4 mmol) was added thereto, the mixture was stirred at room temperature overnight, then water (60 ml) was added to the reaction mixture, and the whole was extracted with ethyl acetate (100 ml). The ethyl acetate layer was washed with 1 N hydrochloric acid (30 ml) and saturated brine (30 ml) successively and dehydrated with anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the obtained oily matter was purified by silica gel column chromatography (mobile phase:hexane/ethyl acetate=3/1) to give 7.72 g (57%) of the target compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][C:9]([F:14])([CH2:11][CH2:12][CH3:13])CC[N:6]1[C:15](OC(C)(C)C)=O)=[O:4].O.[OH-].[Li+].[CH2:25]1COCC1>O>[F:14][C:9]1([CH2:11][CH2:12][CH2:13][CH3:25])[CH2:15][NH:6][C@H:5]([C:3]([OH:2])=[O:4])[CH2:10]1
Reactant: C1CCOC1
Reactant: CCCC1(F)CCN(C(=O)OC(C)(C)C)C(C(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCC1(F)CN[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 12c (0.27 g, 0.89 mmol) in THF (10 mL) and water (3 mL) was added lithium hydroxide monohydrate (45 mg, 1.06 mmol). The reaction mixture was stirred at room temperature overnight. THF was removed and the residue was purified by column chromatography using 10% MeOH in DCM as eluent to obtain 4-Fluoro-4-butylproline 12d (P=Boc, m=1, R9=n-butyl) (0.26 g, 100%) as a colorless oil: 1H NMR (300 MHz, CD3OD) δ 4.30 (m, 1), 3.72 (m, 1), 3.49 (m, 1), 3.39 (m, 1), 2.58 (m, 1), 2.02 (m, 2), 1.72 (m, 13), 0.93 (t, J=6.6, 3); MS (ESNEG): 288 [M−1]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH2:4][O:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:16])[O:6][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH2:4][O:3]1
Reactant: [H][H]
Reactant: CC1(C)OC[C@H](c2ccc([N+](=O)[O-])cc2)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC[C@H](c2ccc(N)cc2)O1
Yield: 99.6 %

Procedure:
A mixture of (S)-2,2-dimethyl-4-(4-nitrophenyl)-1,3-dioxolane (3.6 g, 16.1 mmol) and 5% palladium on carbon (50% wet, 700 mg) in methanol (30 mL) was stirred under 1 atm hydrogen atmosphere (H2 balloon) at RT for 16 h. After the reaction mixture was filtered through a pad of Celite, the filtrate was concentrated to afford the title compound (3.1 g, 100%) as a yellow solid. MS (ES+) C11H15NO2 requires: 193, found: 194 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[CH:3]=1.[H-].[Na+].CN(C=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CCOC(C)=O.O>[CH2:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[O:8][C:4]=2[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc2ccc(O)cc2o1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Reaction time: 1 h

Procedure:
A solution of methyl 6-hydroxybenzofuran-2-carboxylate (3.58 g) in THF (30 ml) was slowly added to a suspension of NaH (800 mg) in THF (100 ml) at room temperature, and after stirring for one hour, DMF (35 ml) was added, benzyl bromide (3.77 g) was slowly added and the mixture was stirred for one hour. Water was added to the reaction solution, extraction was performed with AcOEt, and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=10/1) to obtain methyl 6-(benzyloxy)benzofuran-2-carboxylate.