Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([Mg]Cl)(C)C.[CH3:16][C:17]1[C:18](=[O:22])[CH2:19][CH2:20][CH:21]=1>C1COCC1.CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:7]=[C:6]([CH:21]2[CH2:20][CH2:19][C:18](=[O:22])[CH:17]2[CH3:16])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: CC1=CCCC1=O
Reactant: COc1ccc(I)cc1Br
Agent: CC(C)[Mg]Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2CCC(=O)C2C)cc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a 100 mL RBF was added 2-bromo-4-iodo-1-methoxybenzene (0.59 g, 1.87 mmol), and 10 mL THF. iPrMgCl (0.94 mL, 1.89 mmol, 2M THF solution) was added at 0° C. via syringe. The reaction mixture was stirred at 0° C. for 1 hr. A solution of lithium 2-thenyl cyanocuprate (7.5 mL, 1.87 mmol) in THF was added, followed by 2-methylcyclopent-2-enone (150 mg, 1.56 mmol). The resulting reaction mixture was stirred at 0° C. for 1 hr and was allowed to warm up and stirred at rt for 1 hr. The reaction mixture was diluted with 30 mL EtOAc/hexane (1:1), washed with 30 mL 1N HCl, then 20 mL brine. Organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified by silica gel chromatography to give 135 mg 3-(3-bromo-4-methoxyphenyl)-2-methylcyclopentanone as a mixture of two diastereomers at 1.6:1 ratio. 1H NMR for the major diastereomer (500 MHz, CDCl3): δ 7.35 (d, J=2.2 Hz, 1H), 7.05 (dd, J=2.2, 8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.92 (s, 3H), 3.55 (m, 1H), 2.2-2.6 (m, 5H), 0.83 (d, J=7.6 Hz, 3H). 1H NMR for the minor diastereomer (500 MHz, CDCl3): δ 7.48 (d, J=2.1 Hz, 1H), 7.19 (dd, J=2.2, 8.3 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 3.94 (s, 3H), 2.75 (m, 1H), 2.2-2.6 (m, 5H), 1.07 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:18]([O:22][C:23]1[C:24]([CH:29]=O)=[N:25][CH:26]=[CH:27][N:28]=1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:18]([O:22][C:23]1[C:24]([CH2:29][N:15]2[CH2:14][CH2:13][CH:12]([C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH3:2])[CH2:17][CH2:16]2)=[N:25][CH:26]=[CH:27][N:28]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)Oc1nccnc1C=O
Reactant: Cc1ccccc1CC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)C1CCN(Cc2nccnc2OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 67.8 %

Procedure:
After suspending 150 mg of 2-(2-methylphenyl)-1-(piperidin-4-yl)ethanone hydrochloride in 3 ml of dichloromethane, 128 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 188 mg of sodium triacetoxyborohydride were added while stirring on ice, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture to render it alkaline, and then extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (153 mg, 68% yield).
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Cl:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH2:18][N:9]1[C:10]([CH3:14])([CH3:13])[C:11](=[O:12])[N:8]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Reactant: Fc1ccc(CBr)c(Cl)c1
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1ccc(F)cc1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chloro-4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:17][CH:16]=2)[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[O:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:17][CH:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CCCCCCc1ccccc1)c1cnc(-c2ccccn2)o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(CCCCCCc1ccccc1)c1cnc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
7-Phenyl-1-(2-(pyridin-2-yl)oxazol-5-yl)-heptan-1-ol (S2, 20 mg, 0.059) was dissolved in CH2Cl2 (4 mL) and Dess-Martin periodinane (1.5 equiv) was added. The mixture was stirred at room temperature for 2 h before silica gel was added and the reaction mixture was evaporated in vacuo to afford the crude ketone absorbed on silica gel. This mixture was subsequently purified by flash chromatography (SiO2, 10-50% EtOAc-hexanes) to yield the title compound (18 mg, 90%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 8.89 (s, 1H), 8.31 (d, 1H, J=8.0 Hz), 7.99-7.94 (m, 2H), 7.55-7.52 (m, 1H), 7.36-7.33 (m, 2H), 7.26-7.23 (m, 3H), 3.00 (t, 2H, J=7.5 Hz), 2.69 (t, 2H, J=7.5 Hz), 1.87-1.81 (m, 2H), 1.75-1.69 (m, 2H), 1.51-1.47 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 189.4, 162.6, 150.8, 150.7, 145.6, 143.1, 137.6, 134.7, 128.8, 128.7, 126.2, 126.0, 123.8, 39.7, 36.3, 31.7, 29.4 (2C), 24.1; HRMS-ESI-TOF m/z 335.1750 ([M+H]+, C21H22N2O2 requires 335.1754). 1,3,4-Oxadiazoles (4a-4-d, 8a-8h, 20, 27-30) and 1,2,4-Oxadiazoles (9a-9g, 21-24): General Procedure A.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:19][CH3:20])[C:7]2=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH2:41])=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:36]=[N:37][C:38]([NH:41][C:13]3[N:14]=[CH:15][C:10]4[CH:9]=[C:8]([CH2:19][CH3:20])[C:7](=[O:21])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:11]=4[N:12]=3)=[CH:39][CH:40]=2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CCc1cc2cnc(S(C)=O)nc2n(C2CCCC2)c1=O
Solvent: Cc1ccccc1
Product: CCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 105 °C
Yield: 15 %

Procedure:
4-[6-(8-Cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester was prepared by addition of 8-cyclopentyl-6-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.80 g, 2.62 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.82 g, 6.55 mmol) to toluene (10 ml) followed by heating to 105° C. over 10 hours. The resulting suspension was filtered, the solid washed with toluene and dried in vacuo yielding 4-[6-(8-Cyclopentyl-6-ethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester as a solid (0.204 g). MS (APCI); M++1; Calc'd 520.3. Found 520.1.
Reaction SMILES: C([O:4][C@H:5]1[C:31](=O)[CH2:30][C@@:29]2([CH3:33])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@H:27]([O:34]C(=O)C)[CH2:26][C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=O)C.C[O-:40].[Na+]>CO.C1COCC1>[CH3:16][C@@H:15]1[C@:17]2([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]2)[O:18][C@H:13]2[CH2:12][C@@H:11]3[C@@:25]([CH3:38])([C@@H:14]12)[C:26](=[O:40])[C@@H:27]([OH:34])[C@H:28]1[C@H:10]3[CH2:9][CH2:8][C@@H:7]2[C@:29]1([CH3:33])[CH2:30][CH2:31][C@H:5]([OH:4])[CH2:6]2
Reactant: C[O-]
Reactant: CC(=O)O[C@@H]1C[C@@H]2CC[C@@H]3[C@H]([C@H](OC(C)=O)C[C@]4(C)[C@@H]5[C@H](C[C@@H]34)O[C@]3(CC[C@@H](C)CO3)[C@H]5C)[C@@]2(C)CC1=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@H](O)C(=O)[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,11α,25R)-3,11-di(acetoxy)spirostan-2-one was saponified with sodium methoxide in methanol and THF to give the title compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:13])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(O)C.O>[NH2:1][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH3:13]
Reactant: Cc1cc(C#N)ccc1CN=[N+]=[N-]
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCO
Product: Cc1cc(C#N)ccc1CN

Procedure:
The sub-title compound was prepared according to the method described in Example 1(ii) above from 1.4 g (8.1 mmol) of 4-azidomethyl-3-methylbenzonitrile (from step (iv) above) and 2.3 g (9.0 mmol) of triphenylphosphine in 18 mL of ethanol and 2 mL of water. Yield: 0.60 g (contaminated by triphenylphosphine oxide; estimated actual yield: 0.36 g (28%)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25]O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:25][CH2:24][O:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:28][CH:27]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: OCCOc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1CCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (1.7 g, 6.3 mmol), 2-[4-(trifluoromethoxy)phenoxy]ethanol (1.7 g, 7.6 mmol) and triphenylphosphine (3.3 g, 12.7 mmol) in toluene (20 ml) was added DIAD (1.85 ml, 9.5 mmol) dropwise at 0° C. The mixture was left to warm up to RT and stirred overnight. The mixture was then concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield the title product (1.6 g).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=O)(C)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]([NH2:46])[CH3:45])[CH:41]=[CH:42][CH:43]=1>>[NH2:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:21]=1)[C:16]([NH:46][CH:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([Cl:37])[CH:39]=1)[CH3:45])=[O:18]
Reactant: CC(N)c1cccc(Cl)c1
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CC(NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(C2(C#N)CCCC2)c1)c1cccc(Cl)c1

Procedure:
Prepared from 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid and 1-(3-chlorophenyl)ethanamine using a similar procedure as described for the preparation of Example 20. HRMS ES calculated for C32H36ClN3O2: 530.2569, found: 530.2565.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[N:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[N:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(6-fluoropyridin-2-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (300 mg, 0.83 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (156 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (238 mg, 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (293 mg, 66%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:18]([CH2:21][CH3:22])(=[O:20])=[O:19])=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:7])=[O:8])[CH:14]=1
Reactant: [H][H]
Reactant: CCS(=O)(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCS(=O)(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Yield: 89.9 %

Procedure:
A mixture of 40 g of N-tert-butyl-2-ethylsulfonyl-5-nitrobenzenesulfonamide is dissolved in 1500 ml of methanol, 0.5 g of 10% palladium on charcoal is added and the mixture is stirred under a hydrogen atmosphere (1 atmosphere). When the uptake of hydrogen has ended, the catalyst is separated off and the solution is concentrated. 32.9 g of the aniline derivative are thus obtained;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[CH3:18]C(C)(C(OCC)=O)C(OCC)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[C:8]([CH3:18])([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Reactant: CCOC(=O)C(C)(C)C(=O)OCC
Product: CC(C)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2,2-dimethyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl 2,2-dimethyl-malonate.
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: C1CNCCN1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC4CC4)c3n2)cn1
Reaction time: 2.5 h
Yield: 87.6 %

Procedure:
A dimethyl sulfoxide solution (0.8 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (78.3 mg, 0.20 mmol) and piperazine (67.6 mg, 0.78 mmol) was heated at 140° C. and stirred for 2.5 hours. The mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=5:1) to give the title compound (76.5 mg, 89%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:38]1[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]1=[O:39])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 94.3 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone (3.37 g, 7 mmol) and potassium phthalimide (1.94 g, 10.5 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 2-[[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.91 g, 94.4%) as crystals.
Reaction SMILES: Cl.[C:2]1([CH3:18])[CH:7]=[CH:6][C:5]([C:8]([N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)N)=[O:9])=[CH:4][CH:3]=1.[CH3:19][CH2:20][O:21][C:22]([CH:24]1[CH2:30][CH2:29][C:27](=O)[CH2:26][CH2:25]1)=[O:23].C(O)(=O)C.Cl>O>[C:2]1([CH3:18])[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:27]3[CH2:29][CH2:30][CH:24]([C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:25][C:26]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: Cc1ccc(C(=O)N(N)c2ccccc2)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccc(C)cc2)C1

Procedure:
1-(4-Toluoyl)-1-phenylhydrazine hydrochloride (13 g.) and 8.7 g. of ethyl cyclohexanone-4-carboxylate (prepared in situ from the corresponding ethylene ketal) in 40 ml. glacial acetic acid, and 5 ml. glacial acetic acid saturated with hydrogen chloride was warmed on a steam bath for thirty minutes, diluted with water and extracted with ether. The ether extracts were washed with potassium bicarbonate solution and water, dried, and evaporated to dryness. The residue was chromatographed on silica gel using 10% ether-pentane as eluant to give 12.7 g. of the title compound; m.p. 70°-72°C. (hexane-ether).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[CH:4][CH:3]=1.O.C(OCC)C.[CH3:19][N:20](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:19]([C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[OH:12])=[CH:4][CH:3]=1)#[N:20]
Reactant: CN(C)C=O
Reactant: OC1CCCc2ccc(Br)cc21
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc2c(c1)C(O)CCC2
Temperature: 95 °C

Procedure:
To a solution of 7-bromo-1,2,3,4-tetrahydro-naphthalen-1-ol (0.708 g, 3.11 mmol), which can be prepared as described in Example 5, in DMF (6.5 mL) is added zinc cyanide (0.274 g, 2.33 mmol). Four evacuation-nitrogen fill cycles are performed and tetrakis(triphenylphosphine) palladium (0.072 g, 0.062 mmol) is added. The mixture is heated to 95° C. until the reaction is complete, whereupon water and diethyl ether are added. The mixture is filtered through Celite® and the organic phase is washed with water, dried with MgSO4, filtered and concentrated to give 7-cyano-1,2,3,4-tetrahydro-naphthalen-1-ol; 1H NMR (400 MHz, CDCl3) δ ppm 1.76-1.92 (m, 2 H), 1.95-2.13 (m, 2 H), 2.73-2.94 (m, 2 H), 4.77-4.80 (m, 1 H), 7.20 (d, J=8.0 Hz, 1 H), 7.46 (dd, J=8.0, 1.6 Hz, 1 H), 7.79 (br. s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C.O.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCI
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 40 °C
Reaction time: 18 h
Yield: 43.3 %

Procedure:
7-Benzyl-3,7-dihydro-1H-purine-2,6-dione (5.0 g, 21 mmol) was mixed with sodium carbonate (3.3 g, 31 mmol) and 1-iodopentane (4.0 mL, 31 mmol) in DMF (60 mL). After being stirred at 40° C. for 18 h, the reaction mixture was diluted with water and EtOAc. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated. The resulting white solid was collected and dried in vacuum oven at 50° C. for 18 h to provide the desired product (2.84 g, 44% yield). LCMS calculated for C17H21N4O2 (M+H): 313.2. found: 313.2.
Reaction SMILES: [C:1]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[O:13])[CH2:9]2)(OC)=O.[H-].C([Al+]CC(C)C)C(C)C>C1C=CC=CC=1>[CH3:1][N:5]1[CH:10]2[CH2:9][CH:8]([OH:13])[CH2:7][CH:6]1[CH2:12][CH2:11]2
Reactant: COC(=O)N1C2CCC1CC(=O)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: c1ccccc1
Product: CN1C2CCC1CC(O)C2

Procedure:
A process as claimed in claim 8, wherein N-carbomethoxy-8-azabicyclo (3,2,1) octan-3-one is reacted with diisobutyl-aluminumhydride in benzene and at room temperature, to produce tropine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([S:19](Cl)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)#[N:12]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][S:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:11]#[N:12])[CH:14]=2)(=[O:21])=[O:20])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Reactant: NCCc1ccc(Br)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(S(=O)(=O)NCCc2ccc(Br)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 2-(4-bromophenyl)ethanamine (600 mg, 3.13 mmol) and TEA (800 mg, 8 mmol) in THF (10 mL), was added a solution of 3-cyano-benzenesulfonyl chloride (580 mg, 2.88 mmol) in THF (10 mL) at 0° C. The mixture was stirred at rt for 2 h, quenched with water, and extracted with EtOAc (3×20 mL). The organic layer washed with brine, dried (Na2SO4) and concentrated. Purification via flash chromatography (0-50% EtOAc in hexanes) gives 68A (708 mg, 71%). MS (ESI) m/z 365.3 (M+H)+.