Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]([CH:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][NH:15]3)[CH:9]=[CH:10][C:2]1=2.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:33](C)=O.[Na+].CC(O)=O>ClCCCl.C(OCC)(=O)C.[OH-].[Na+]>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]([CH:20]3[CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH3:33])[CH:9]=[CH:10][C:2]1=2
Reactant: c1ccc2c(c1)CC(N(CCC1CCCCN1)c1ccc3c(c1)OCCO3)C2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CN1CCCCC1CCN(c1ccc2c(c1)OCCO2)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of compound 60 (0.5 g, 1.32 mmol) in DCE (25 mL) were added formaldehyde (35% solution in H2O, 0.17 mL, 1.98 mmol), Na(OAc)3BH (0.84 g, 3.96 mmol) and AcOH (0.2 mL) successively at 0° C. and the mixture was stirred at rt for 16 hours. The reaction mixture was dissolved in ethyl acetate and basified with 1N NaOH. The organic layer was separated and washed with water and brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated. The crude material was purified by Combiflash® chromatography eluting with 5-5.2% methanol-DCM to provide compound 61.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:16][CH2:15][C:14]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)=[CH:13][CH2:12]1)[CH3:10])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)(=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([C:26]([N:28]1[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29]1)=[O:27])[C@H:9]([CH:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:22]3[N:23]=[CH:24][N:25]=[C:21]3[CH:20]=[CH:19][CH:18]=2)[CH2:15][CH2:16]1)[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C1CC=C(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](C1CCC(c2cccc3ncnn23)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
The material from Step B (0.13 g, 0.27 mmol) was hydrogenated at 50 psi hydrogen in the presence of 10% palladium on carbon (0.13 g) in methanol (5 mL) containing 30 drops of acetic acid using a Parr shaker. After 1 h, the reaction mixture was filtered by passage through a syringe filter. The filtrate was concentrated and the residue was dissolved in chloroform and washed with saturated aqueous sodium bicarbonate. The organic layer was dried (anhydrous sodium sulfate) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-5% methanol in dichloromethane) gradient to afford the title compound. LC/MS 492.1 (M+1).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CCOC(C)=O.[CH3:17][N:18](C=O)[CH3:19]>>[CH3:17][N:18]([CH3:19])[C:6]([C:5]1[CH:9]=[CH:10][C:2]([SH:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(S)cc1
Temperature: 150 °C

Procedure:
Di-Phosphorous pentoxide (923 mg) was added to a solution of 4-mercaptobenzoic acid (2000 mg) in DMF (10 ml). The mixture was stirred for sixteen hours at 150° C. under argon. The mixture was allowed to cool then EtOAc (150 ml) was added. The solution was washed with water (100 ml), brine (50 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography on silica gel, eluted with 2.5% MeOH in DCM to give two samples. One sample containing a mixture of thiol and disulphide was purified by chromatography on silica gel, eluted with 1-2.5% MeOH in DCM to give the title compound (760 mg) as a solid. NMR: 2.94 (s, 6H), 5.63 (s, 1H), 7.30 (m, 4H); m/z 180.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:38](=[CH2:40])=[N-:39]>C1COCC1.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](=[O:12])[CH:40]=[N+:38]=[N-:39])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc([N+](=O)[O-])cc1)C(=O)C=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 82.3 %

Procedure:
To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid (1.20 g, 4.0 mmol) in THF (20 mL) is added dropwise triethylamine (0.61 mL, 4.4 mmol) followed by iso-butyl chloroformate (0.57 mL, 4.4 mmol). The reaction mixture is stirred at 0° C. for 20 minutes then filtered. The filtrate is treated with an ether solution of diazomethane (˜16 mmol) at 0° C. The reaction mixture is stirred at room temperature for 3 hours and concentrated. The residue is dissolved in EtOAc and washed successively with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue is purified over silica (hexane/EtOAc 2:1) to afford 1.1 g (82% yield) of the desired product as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.16 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz, 2H), 5.39 (s, 1H), 5.16 (d, J=6.3 Hz, 1H), 4.49 (s, 1H), 3.25 (dd, J=13.8 and 6.6, 1H), 3.06 (dd, J=13.5 and 6.9 Hz, 1H), 1.41 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[I-:12].[Na+].[I-].O>C(O)CCC.[Cu]>[I:12][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: [I-]
Reactant: Brc1ccc2ncccc2c1
Agent: [Cu]
Agent: [Na+]
Solvent: O
Solvent: CCCCO
Product: Ic1ccc2ncccc2c1
Temperature: 120 °C
Yield: 80 %

Procedure:
6-bromoquinoline (80.1 g, 0.385 mol) is dissolved in n-butanol (0.8 L). Copper catalyst CuI (3.7 g, 0.019 mol), a copper-ligand N,N′-dimethylethylenediamine (3.4 g, 0.0385 mol) and an iodide source NaI (115.5 g, 0.770 mol) are added and the mixture is heated in a heating jacket, under inert atmosphere to 120° C. After work-up (0.8 L water is added to the reaction mixture, the organic layer is separated off and evaporated) and purification (the crude evaporation residue was crystallized from 150 mL diisopropylether), 6-iodoquinoline was obtained in 80% yield.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH2:9]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:16]2[N:27]=[CH:28][CH:29]=[C:15]2[N:14]=1)[CH2:10][CH2:11][CH3:12].O>COCCOC.O>[Br:8][C:29]1[CH:28]=[N:27][N:16]2[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][C:13]([CH2:9][CH2:10][CH2:11][CH3:12])=[N:14][C:15]=12
Reactant: CCCCc1cc(OCc2ccncc2)n2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: COCCOC
Product: CCCCc1cc(OCc2ccncc2)n2ncc(Br)c2n1
Reaction time: 1 h
Yield: 93.8 %

Procedure:
NBS (0.38 g) was added to a solution of 0.5 g of 5-n-butyl-7-(4-pyridylmethoxy)pyrazolo[1,5-a]pyrimidine in 10 ml of DME-water (3:1) at 0° C. and stirred for 1 hour. The mixture was stirred at room temperature for another 2 hours to allow the reaction to proceed. Some water was added to the reaction mixture, and the crystals precipitated were collected by filtration to provide 0.6 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=[C:4]([O:13][CH2:14][CH2:15][O:16][CH3:17])[N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCCC1>[Cl-:1].[CH3:17][O:16][CH2:15][CH2:14][O:13][C:4]1[N:5]=[C:6]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:7]=[C:2]([N+:19]2([CH3:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: CN1CCOCC1
Reactant: COCCOc1nc(Cl)nc(OCCOC)n1
Solvent: C1CCOC1
Product: COCCOc1nc(OCCOC)nc([N+]2(C)CCOCC2)n1
Product: [Cl-]
Reaction time: 0.5 h
Yield: 34 %

Procedure:
To 1.05 g (4 mmole) of 2-chloro-4,6-di-(2-methoxyethoxy)-1,3,5-triazine (obtained as described in Example 1) in 3.5 mL of dry tetrahydrofuran was added 530 μL of N-methyl morpholine. The solution was stirred for 30 minutes, filtered, and dried in an Abderhalden apparatus using acetone for 12 hours to yield 0.5 g (34%) of 4-(4,6-di-(2-methoxyethoxy)-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride as a white powder. IR spectroscopy of the product (neat) identified the following characteristic IR absorption frequencies: 1605 cm−1, 1417 cm−1, 1336 cm−1, 1300 cm−1, 1118 cm−1, 1094 cm−1, 1068 cm−1, 1053 cm−1, 1028 cm−1, 1009 cm'1, 991 cm−1, 972 cm−1, 858 cm−1, and 821 cm−1.
Reaction SMILES: C([O:3][CH2:4][C:5]1[N:6](CCC(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)C.C(N1[C:40]2[C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3N=C(N)C=2N=C1CCOC)CCC.C(N1C2C3C=CC=CC=3N=C(N)C=2N=C1COCC)CCC.NC1C2N=C(CO)N(CCCC)C=2C2C=CC=CC=2N=1>>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][OH:3])[N:6]([CH2:40][C:39]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCC(C)C
Reactant: CCCCn1c(CCOC)nc2c(N)nc3ccccc3c21
Agent: CCCCn1c(CO)nc2c(N)nc3ccccc3c21
Agent: CCCCn1c(COCC)nc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1nc(CO)n2Cc1ccccc1

Procedure:
A compound according to claim 1, selected from the group consisting of 2-ethoxymethyl-1-(3-methylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine, 1-butyl-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine, 1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine, and 4-amino-1-butyl-1H-imidazo[4,5-c]quinoline-2-methanol,
Reaction SMILES: CN.[C:3]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12](O)=O)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:18]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=O)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C1C=CC2N(O)N=[N:41]C=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C)C=O>[O:34]=[C:32]([NH:41][CH2:12][C@@H:11]1[CH2:15][CH2:16][CH2:17][N:10]1[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:31][CH2:30][CH2:29][NH:28][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(O)CCCNC(=O)OCc1ccccc1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNC(=O)CCCNC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 82.9 %

Procedure:
Part B N-BOC-L-proline methylamine (1.04 g, 5.2 mmol) and N-CBZ-4-aminobutyric acid (1.24 g, 5.2 mmol) were dissolved in dimethyl formamide (DMF) (20 mL) at room temperature (RT). HOBT (702 mg, 5.2 mmol), WSC (995 mg, 5.2 mmol) and NMM (570 μL, 5.2 mmol) were added. The reaction was stirred for 16 hours (h), partitioned between ethyl acetate(50 mL) and 10% KHSO4 (100 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL), and the organic layers were combined. The combined organic layers were washed with saturated NaHCO3 (50 mL) and saturated NaCl (50 mL), dried over magnesium sulfate and concentrated in vacuo to provide an oil. The crude material was purified by chromatography on silica gel. Elution with ethyl acetate:hexanes(2:1) followed by ethyl acetate gave title compound, (1.809 g, 83%) as a viscous oil which was characterized by NMR and used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[NH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>O1CCCC1>[CH2:48]([O:47][C:45](=[O:46])[CH2:44][CH2:43][CH2:42][NH:41][C:18](=[O:20])[CH2:17][N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH3:49]
Reactant: CCOC(=O)CCCN
Reactant: O=C(O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCNC(=O)Cn1c(-c2cccc(Cl)c2)nc2cccnc21
Yield: 16.9 %

Procedure:
A solution of 2-(3-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (8.0 g, 0.028 mole), 1,1'-carbonyldiimidazole (4.5 g, 0.028 mole), and anhydrous tetrahydrofuran (100 ml) was stirred at room temperature with a stream of nitrogen bubbling through it for 3 hours. The nitrogen flow was stopped and triethylamine (6.3 g, 0.062 mole) and ethyl 4-aminobutyrate hydrochloride (5.2 g, 0.031 mole) were added all at once. The reaction mixture was stirred under nitrogen over the weekend. The tetrahydrofuran was evaporated and the solid residue triturated in water (100 ml) and filtered off to give 4.7 g (42%) of cake. A 2.3-g portion of the filter cake was recrystallized from isopropyl ether-ethanol to give 1.9 g of white solid, mp 127°-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34](Cl)=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=1>CCCCCCC.C(OCC)(=O)C>[CH3:28][O:29][C:30](=[O:42])[C:31]1[CH:36]=[CH:35][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([C:38]([F:39])([F:41])[F:40])[CH:32]=1
Reactant: COC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 4-chloro-3-trifluoromethyl-benzoic acid methyl ester (commercially available) after a reaction time of 6 h and using a gradient of n-heptane:Ethyl acetate (100:0 to 60:40). White solid (32%). MS (Turbo Spray): m/z=493.3 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:15]([F:18])([F:17])[F:16])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#N)=[CH:8][CH:7]=[CH:6]2.[OH-:19].[K+].C[OH:22]>O>[CH3:1][O:2][C:3]1[C:4]([C:15]([F:18])([F:17])[F:16])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([OH:22])=[O:19])=[CH:8][CH:7]=[CH:6]2
Reactant: CO
Reactant: [OH-]
Reactant: COc1ccc2c(C#N)cccc2c1C(F)(F)F
Agent: [K+]
Solvent: O
Product: COc1ccc2c(C(=O)O)cccc2c1C(F)(F)F
Temperature: 130 °C
Reaction time: 5.5 h
Yield: 100 %

Procedure:
A solution of 0.5 g of 6-methoxy-5-trifluoromethyl-1-cyanonaphthalene and 0.6 g of potassium hydroxide in 25 ml of a 20/5 mixture of methanol and water was charged into an autoclave, heated to 130° C. and stirred for 5-6 hours at an internal pressure of 90-100 psi. The reaction mixture was then cooled and worked up to provide a 98% recovered yield of 100% pure 6-methoxy-5-trifluoromethyl-1-naphthoic acid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:5]2[N:15]=[C:16]([C:18]3[C:27]([CH3:28])=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:17]=[C:4]2[N:3]=1.[C:29]1(B(O)O)[CH2:33][CH2:32][CH2:31][CH:30]=1.[F-].[Cs+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]1([C:2]2[CH:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[N:5]3[N:15]=[C:16]([C:18]4[C:27]([CH3:28])=[N:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:17]=[C:4]3[N:3]=2)[CH2:33][CH2:32][CH2:31][CH:30]=1
Reactant: OB(O)C1=CCCC1
Reactant: Cc1nc2ccccc2nc1-c1cc2nc(Cl)cc(NC3CCOCC3)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: Cc1nc2ccccc2nc1-c1cc2nc(C3=CCCC3)cc(NC3CCOCC3)n2n1
Temperature: 80 °C

Procedure:
A suspension of 5-chloro-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (Example 1.001 (g)) (97 mg, 0.246 mmol), cyclopenten-1-ylboronic acid (55 mg, 0.491 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.0493 mmol), and cesium fluoride (112 mg, 0.737 mmol) in 1,2-dimethoxyethane (2.0 mL) was heated at 80° C. for 3 h. After being cooled to ambient temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=9:1 to 2:3) to give 5-cyclopent-1-en-1-yl-2-(3-methylquinoxalin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (the compound of Example 1.011 listed in the Table of Examples as described hereinafter). 1H-NMR (400 MHz, CDCl3): δ 1.73-1.86 (2H, m), 2.03-2.21 (4H, m), 2.60-2.66 (2H, m), 2.86-2.93 (2H, m), 3.05 (3H, s), 3.61 (2H, ddd, J=11.8, 11.8, 2.4 Hz), 3.77-3.87 (1H, m), 4.10 (2H, ddd, J=11.8, 3.3, 3.3 Hz), 6.19 (1H, s), 6.33 (1H, d, J=8.2 Hz), 6.68 (1H, s), 7.08 (1H, s), 7.72-7.79 (2H, m), 8.04-8.08 (1H, m), 8.17-8.21 (1H, m).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:10][OH:11]>F[P-](F)(F)(F)(F)F.C([N+](CCC)(CCC)CCC)CC>[C:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[O:11][CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCCCC1
Reactant: CO
Agent: CCC[N+](CCC)(CCC)CCC
Agent: F[P-](F)(F)(F)(F)F
Product: COC1CCCCN1C(C)=O
Yield: 80.5 %

Procedure:
In the same manner as indicated in Example 6 there are electrolyzed 21.6 g of N-acetylpiperidine and 54.4 g of methanol in the presence of 0.56 g of tetra-n-propylammonium hexafluorophosphate as conducting salt. After throughput of 2.0 Faraday per mol of N-acetylpiperidine the current is switched off. The calculated mean cell voltage is 28.7 volts. Work-up of the electrolysis solution by molecular distillation gives 21.5 g of 1-acetyl-2-methoxypiperidine, which corresponds to a product yield of 80.5% and a current efficiency of 80.5%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.[NH2:39][C:40]1[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:46][C:41]1[C:40]([NH:39][C:35]([CH:16]2[CH:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17]2)=[O:36])=[CH:45][CH:44]=[CH:43][N:42]=1
Reactant: Cc1ncccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncccc1NC(=O)C1NC(CC(C)(C)C)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Yield: 55.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 52c (0.3 g, 0.52 mmol) was reacted with 3-amino-2-methyl-pyridine (Aldrich) (0.11 g, 1.1 mmol), HATU (0.36 g, 0.94 mmol) and iPr2NEt (0.27 g, 1.6 mmol) in CH2Cl2 at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (2-methyl-pyridin-3-yl)-amide as a yellow solid (0.16 g, 55%).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)(=O)CCC=C>ClCCl>[O:5]=[C:4]([CH2:15][CH2:14][CH:13]=[CH2:12])[CH2:6][C:7]([O:9][CH3:2])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: c1ccncc1
Agent: C=CCCC(=O)Cl
Solvent: ClCCl
Product: C=CCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 40 %

Procedure:
To a solution of Meldrum's acid (22.0 g) and pyridine (25.0 ml) in dichloromethane (100 ml) was added dropwise pent-4-enoyl chloride (18.5 ml) under ice-cooling. The reaction mixture was stirred at room temperature for 10 hr, and washed with water and 1M hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in methanol (150 ml), and the mixture was stirred with heating under reflux for 8 hr. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (hexane/ethyl acetate=10/1 to hexane/ethyl acetate=5/1) to give the title compound as a pale-yellow liquid (4.57 g, 40%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Br:7])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br-:7].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P+:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 90.4 %

Procedure:
A solution of 4-fluoro-3-phenoxybenzyl bromide (42.17 g, 0.150 mol) in toluene is added to a solution of triphenyl phosphine (41.31 g, 0.158 mol) in toluene. The resultant reaction mixture is refluxed for one hour, cooled to room temperature, and filtered to obtain a solid. The solid is washed sequentially with toluene and hexanes, and dried in a dessicator at 60° C. to give the title product (73.7 g, 90.4%) which is identified by NMR spectral analyses.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20]CC)=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 77 %

Procedure:
Benzyl chloroformate (8.5 g) was added dropwise to a stirred mixture of ethyl piperidine-4-carboxylate (7.85 g), triethylamine (6.95 ml) and methylene chloride (50 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The organic phase was washed with water and with brine, dried (MgSO4) and evaporated. The residue was dissolved in methanol (100 ml) and 2N aqueous sodium hydroxide (125 ml) was added. The mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated by evaporation and the residue was partitioned between diethyl ether and water. The aqueous phase was acidified to pH3 by the addition of concentrated hydrochloric acid and the mixture was extracted with ethyl acetate. The organic extract was washed with water, dried (MgSO4) and evaporated to give 1-benzyloxycarbonylpiperidine-4-carboxylic acid (10.1 g).