Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[N:2]1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)C(C)C)(C)C.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:51]3[N:56]=[C:55]([CH2:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=4[CH:65]([CH3:69])[C:66]([O-])=[O:67])[C:54]([C:70]([F:73])([F:72])[F:71])=[CH:53][N:52]=3)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[Li+].C(=O)([O-])[O-].[NH4+].[NH4+]>C1COCC1.CN(C=O)C>[NH2:2][C:66](=[O:67])[CH:65]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][C:59]=1[CH2:58][CH2:57][C:55]1[C:54]([C:70]([F:72])([F:73])[F:71])=[CH:53][N:52]=[C:51]([NH:50][C:47]2[CH:48]=[CH:49][C:44]([CH:41]3[CH2:42][CH2:43][N:38]([C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH2:39][CH2:40]3)=[CH:45][CH:46]=2)[N:56]=1)[CH3:69]
Reactant: On1nnc2ccccc21
Reactant: CC(C(=O)[O-])c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-Hydroxybenzotriazole (21.1 mg, 0.156 mmol), EDCI (30.0 mg, 0.156 mmol) and N,N-diisopropylethylamine (54.5 μL, 0.313 mmol) were added to a solution of lithium 2-(2-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)propanoate (I54) (0.086 g, 0.142 mmol) in dry THF (6 mL) and dry DMF (1 mL) under an atmosphere of nitrogen. Ammonium carbonate (54.6 mg, 0.569 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (50 mL) then washed with saturated NaHCO3 (50 mL). The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed in vacuo to afford a pale yellow solid. The crude material was purified by column chromatography on silica gel (0-85% EtOAc in petroleum benzine 40-60° C.) to afford the title compound (I55) (65.2 mg, 77%) as a white foamy solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](OS(C(F)(F)F)(=O)=O)[C:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:5]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[CH3:33][NH:34][CH:35]([CH3:37])[CH3:36]>>[C:23]([O:22][C:20]([C:6]1[C:7]([N:34]([CH:35]([CH3:37])[CH3:36])[CH3:33])=[N:8][C:9]2[C:4]([C:5]=1[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)=[O:21])([CH3:25])([CH3:24])[CH3:26]
Reactant: CNC(C)C
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CC(C)N(C)c1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 92 step A from tert-butyl 6-chloro-4-phenyl-2-(trifluoromethylsulfonyloxy)quinoline-3-carboxylate (prepared in analogy to example 91 step A to C, 100 mg, 0.21 mmol) and N-methylpropan-2-amine (0.213 ml, 2.05 mmol). Pale yellow solid (75 mg, 89%). MS (ESI): 411 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[O:6][CH:5]1[C:7]([OH:9])=O)[CH2:2][CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.[CH:25]1([NH2:28])[CH2:27][CH2:26]1.[OH-].[Na+]>C(OC(C)C)(=O)C>[CH:25]1([NH:28][C:7]([CH:5]2[CH:4]([CH2:1][CH2:2][CH3:3])[O:6]2)=[O:9])[CH2:27][CH2:26]1
Reactant: CCCC1OC1C(=O)O
Reactant: NC1CC1
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: CC(=O)OC(C)C
Product: CCCC1OC1C(=O)NC1CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
A flask equipped with an overhead stirrer, thermometer and addition funnel was placed under a nitrogen atmosphere then charged with the acid of Example 1 (20.0 g, 154 mmol), and isopropyl acetate (IPAc; 200 mL) then cooled to 0±5° C. 4-Methylmorpholine (NMM, 154 mL, 17 mL) was charged to the addition funnel then added maintaining the temperature at 0±5° C. Once addition was complete the addition funnel washed with IPAc (10 mL) and then charged with isobutyl chloroformate (IBCF, 137 mmol, 19.5 mL) which was added keeping the temperature at 0±5° C. The reaction mixture was stirred at 0±5° C. for 90 min after which time a solution of cyclopropylamine (154 mmol, 10.7) in IPAc (80 mL) was added keeping the temperature at 0±5° C. Upon completion of addition the reaction was warmed to 25±5° C. and allowed to stir for 18 h. Sodium hydroxide (231 mL, 1.0 N) was added and the biphasic mixture stirred vigorously for 30 min, then the layers were separated. The organic phase was then washed with HCl (231 mL, 1.0 N). The combined organic phases were dried over sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure to provide the title compound (19.5 g, 75%) as an orange oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH2:13]O)[CH:10]=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:17])=O>>[Cl:17][CH2:13][C:9]1[CH:10]=[N:11][CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=1
Reactant: OCc1cncc(-c2ccccc2)c1
Reactant: O=S(Cl)Cl
Product: ClCc1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of 5-phenyl-3-pyridylmethanol (4.50 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloromethyl-5-phenylpyridine (4.28 g, yield 86%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from ethyl acetate-hexane. Melting point: 75–76° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[CH2:14]>>[Cl:1][C:2]1[N:3]([C:18]2[CH:19]=[CH:20][C:15]([CH:13]=[CH2:14])=[CH:16][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: C=Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 28 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-vinylphenylboronic acid as described in step 1 of Example 29 to afford 2-chloro-1-(4-vinylphenyl)-1H-indole-3-carboxaldehyde (28% yield) as a off white solid. ESI/MS 282 (M+H); RT=3.59 min; NMR 10.22 (1H, s); 8.36 (1H, d, J=6 Hz); 7.65 (2H, d); 7.37 (5H, m); 6.87 (1H, dd); 5.92 (1H, d, J=18 Hz); 5.45 (1H, d, J=12 Hz).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1>CO.[Pd]>[CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1
Reactant: CNCCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CNCCc1ccc(N)cc1

Procedure:
Prepared by catalytic hydrogenation of 4-(2-methylamino-ethyl)-nitrobenzene over palladium-charcoal in methanol analogously to Example 39c.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([Cl:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH:19]([CH3:21])[CH2:18][NH:17][CH2:16]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([Cl:12])=[C:10]([N:17]2[CH2:18][CH:19]([CH3:21])[CH2:20][CH:15]([CH3:14])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CNCC(C)C1
Reactant: CC#CCOc1ncnc(Cl)c1Cl
Solvent: CCO
Product: CC#CCOc1ncnc(N2CC(C)CC(C)C2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-5,6-dichloropyrimidine, 0.47 g of 3,5-dimethylpiperidine (cis/trans=about 3/1) was added therein, and the mixture was stirred for 8 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.36 g of 4-(2-butynyloxy)-5-chloro-6-(3,5-dimethylpiperidino)pyrimidine (hereinafter, referred to as Compound (8)). Compound (8) had the cis/trans diastereomer originated two methyls on the piperidine ring. The ratio of the cis/trans diastereomer was about 3.6/1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]=2)[CH2:13][CH2:14]1
Reactant: COC(=O)C1CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C1CC=C(N2CCOCC2)CC1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
In a round-bottom flask equipped with a Dean-Starke trap, 15.6 g of methyl 4-oxocyclohexanecarboxylate, 0.1 mol), morpholine (9.63 mL, 0.11 mol) and p-toluenesulfonic acid (5 mg) in benzene (42.3 mL) was heated up to reflux. Water was removed and the reaction was continued at reflux for 8 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to give crude product as a yellow oil (20 g), which was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(NCCCCOCc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN(CCCCOCc1ccccc1)c1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
3-(4-Benzyloxybutylamino)benzonitrile (0.22 g) and potassium carbonate (0.21 g) were suspended in N,N-dimethylformamide (5 mL). To the reaction mixture was added methyl iodide (0.16 g), and the mixture was stirred at 50° C. for 16 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give the title compound (0.22 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]3=[O:28])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.Cl>C(Cl)(Cl)Cl.C(OCC)C>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[O:21][C:20]3=[O:28])[CH2:16][CH2:17][C@@H:10]12
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](Cn3c(=O)oc4ccccc43)CC[C@H]2C1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: O=c1oc2ccccc2n1C[C@@H]1CC[C@H]2CNCCN2C1
Yield: 99.9 %

Procedure:
A solution of 3.1 g (8.01 mmol) of 3-[(7R,9aS)-2-BOC-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]-pyrazin-7-ylmethyl]-3H-benzooxazol-2-one in 40 mL of chloroform was stirred with excess HCl (g) in ethyl ether for 2 h at ambient temperature. The solvent was evaporated to give 2.3 g (100%) of the title compound dihydrochloride which was used for subsequent reactions without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C(OCC)C>[C:12]([O:11][C:9](=[O:10])[CH2:8][NH:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCCCCO
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CNCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold (0° C.) solution of 4-hydroxybutylamine (9.1 g, 101.8 mmol) in diethyl ether (100 mL), a solution of tert-butyl bromoacetate (7.4 g, 49.3 mmol) in diethyl ether (25 mL) was added dropwise over a period of 2 hours. The reaction mixture was allowed to warm up slowly to room temperature and stirred at the temperature overnight. The product mixture was washed successively with aqueous NaHCO3, water, and brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. This intermediate was used in the following reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:3][CH2:2]1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]([C:25]2[CH2:26][CH2:27][N:22]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:23][CH:24]=2)=[CH:9][NH:10]3)[CH2:2][CH2:3]1
Reactant: c1cc(OCC2CC2)c2cc[nH]c2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Product: C1=C(c2c[nH]c3cccc(OCC4CC4)c23)CCN(Cc2ccccc2)C1
Yield: 23.3 %

Procedure:
Beginning with 3.77 gm (20.1 mMol) 4-cyclopropylmethyloxy-1H-indole and 7.5 mL (40.3 mMol) 1-benzyl-4-piperidone, 1.68 gm (23%) of the title compound were recovered as an off white solid.
Reaction SMILES: C(O[C:5](=[O:22])[NH:6][CH:7]1[CH2:11][C:10](=[O:12])[O:9][CH:8]1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C=C.CC1C2C(=CC=CC=2)C(C)=C2C=1C=CC1C2=CC=CC=1.[NH2:43][C:44]1[CH:64]=[CH:63][C:47]([C:48]([NH:50][CH:51]([CH3:62])[C:52]([N:54]2[CH2:58][CH2:57][CH2:56][CH:55]2C(O)=O)=[O:53])=[O:49])=[CH:46][C:45]=1[Cl:65].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.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>[O:12]=[C:10]1[O:9][CH:8]([O:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]([NH:6][C:5]([CH:55]2[CH2:56][CH2:57][CH2:58][N:54]2[C:52](=[O:53])[CH:51]([NH:50][C:48](=[O:49])[C:47]2[CH:63]=[CH:64][C:44]([NH2:43])=[C:45]([Cl:65])[CH:46]=2)[CH3:62])=[O:22])[CH2:11]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1c2ccccc2c(C)c2c1ccc1ccccc12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
To a solution of (5-oxo-2-phenethyloxy-tetrahydro-furan-3-yl)-carbamic acid allyl ester (194 mg, 0.54 mmol) (prepared as described for (40) using phenethyl alcohol) in anhydrous CH2Cl2 (5 mL) at 0° C. was added DMBA (196 mg, 1.26 mmol) and Pd(PPh3)4 (32 mg, 0.03 mmol). The solution was stirred for 15 min and a solution of 97a (prepared from 96a by treatment with TFA in CH2Cl2) (166 mg, 0.49 mmol) and DIEA (680 μl, 3.90 mmol) in CH2Cl2 (2 mL) was added followed by HOBT (98 mg, 0.73 mmol) and EDC (122 mg, 0.63 mmol). The solution was stirred at 0° C. for 15 min then at room temperature for 18 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc then washed with 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine. Dried over anhydrous Na2SO4 and evaporated to give an orange solid which was purified by flash column chromatography, using CH2Cl2/MeOH (99/1 to 97/3%) to yield the title compound as a white solid (190 mg, 73% yield). 1H-NMR (500 MHz, CD3OD) δ 1.29 (d, 0.6H), 1.41 (d, 2.4H), 1.78 (m, 1H), 2.08 (m, 3H), 2.56 (m, 1H), 2.77 (dd, 1H), 2.94 (t, 2H), 3.53 (m, 0. 3H), 3.67 (m, 0.8H), 3.85 (m, 2H), 3.96-4.08 (m, 1H), 4.40 (m, 2H), 4.62 (m, 1H), 4.67-4.79 (m, 1H), 5.57 (d, 0.7H), 5.60 (d, 0.3H), 6.78 (dd, 1H), 7.21 (m, 5H), 7.58 (m, 1H), 7.79 (m, 1H), 8.26 (d, 1H). Analytical HPLC 14.52 min. LC-MS (ES+) m/e=543.2 (MH+).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH:15]([NH2:18])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:18][CH:15]([CH3:17])[CH3:16])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(C)C)c([N+](=O)[O-])c1
Yield: 81.4 %

Procedure:
4-Isopropylamino-3-nitro-benzoic acid methyl ester (900.0 mg) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (1.0 g) and isopropyl amine (325.0 mg) in DMF (10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)=[O:7]>[Ni].CO>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([O:8][CH:9]1[CH2:10][C:11]([CH3:18])([CH3:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH2:14]1)=[O:7]
Reactant: CC1(C)CC(OC(=O)c2ccco2)CC(C)(C)N1
Agent: [Ni]
Solvent: CO
Product: CC1(C)CC(OC(=O)C2CCCO2)CC(C)(C)N1
Reaction time: 6 h
Yield: 75.5 %

Procedure:
15 g of 2,2,6,6-tetramethyl-4-piperidyl furan-2-carboxylate, 150 ml of methanol and 3 g of Raney nickel are introduced into a 0.3 l hydrogenation autoclave, and hydrogenation is carried out at 100° C. and under 100 bar until the pressure remains constant, which takes about 6 hours. The Raney nickel is filtered off, the filtrate is evaporated down and the residue is distilled under reduced pressure to give 11.5 g of a colorless oil of boiling point 118°-122° C./1.3 mbar.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:43])([F:42])[C:9]1[CH:10]=[C:11]([C@H:19]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][OH:29])[C@@H:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C@@H:23]2[C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH3:20])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C>ClCCl>[F:42][C:8]([F:7])([F:43])[C:9]1[CH:10]=[C:11]([C@H:19]([O:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH:28]=[O:29])[C@@H:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C@@H:23]2[C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)[CH3:20])[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: CCOC(=O)[C@@H]1[C@@H](CO)CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C=O
Reaction time: 0.08 h
Yield: 9.8 %

Procedure:
To a solution of oxalyl chloride (0.22 mL, 2.6 mmol) in 40 mL dichloromethane was slowly added under nitrogen DMSO (0.13 mL, 1.8 mmol) at −78° C. The mixture was stirred for 5 min at the same temperature. Intermediate alcohol obtained from Step B (0.46 g, 8.6 mmol) in 15 mL dichloromethane was added by injection. Stirring continued at −78° C. for 20 min. Triethylamine (0.48 mL, 3.4 mmol) was added. The cooling bath was removed and the mixture was stirred until the temperature rose to −0° C. The reaction was quenched with sat. aq. NH4Cl. The organic layer was separated and the aqueous was extracted with dichloromethane (40 mL×2). The combined organic extracts were washed with brine, dried over MgSO4, filtered and the solvent was removed under vacuum to give 0.45 g title compound which was used without further purification. 1H-NMR (CDCl3): δ: 9.64 (1H, s), 7.71 (1H, s), 7.22 (2H, s), 7.00 (2H, m), 6.86 (2H, m), 4.43 (1H, q, J=6.4 Hz), 3.80 (2H, q, J=7.1 Hz), 3.34 (1H, m), 2.84 (2H, m), 2.66 (1H, m), 2.46 (1H, m), 2.32 (1H, m), 1.64 (2H, m), 1.42 (1H, m), 1.35 (3H, d, J=6.4 Hz), 0.82 (3H, t, J=7.1 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1.CS(C)=O.[C-:25]#[N:26].[Na+].Cl[O-].[Na+]>O>[C:25]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:20])[CH2:11][CH2:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1)#[N:26]
Reactant: [C-]#N
Reactant: CC(CCCC1CCCCC1)c1ccc(CCCl)cc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CS(C)=O
Solvent: O
Product: CC(CCCC1CCCCC1)c1ccc(CCC#N)cc1

Procedure:
9 Grams of the 4-[p-(2-chloroethyl)phenyl]pentylcyclohexane, 100 ml of dimethyl sulfoxide ((CH3)2SO) and 23 g of sodium cyanide (NaCN) were stirred together at 140° to 150° C. for 2 hours. After the resulting mixture was cooled, a 10% aqueous sodium hypochlorite (NaClO) solution was added. Further, water was added thereto, and the precipitate was recrystallized from ligroin to obtain 4-[p-(2-cyanoethyl)phenyl]pentylcyclohexane. The melting point of this compound was 44° to 46° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]([C:10]1([CH2:24][OH:25])[CH2:14][C:13](=[O:15])[N:12]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH2:11]1)=[O:9].CCN(CC)CC.O>C1COCC1>[CH3:6][O:7][C:8]([C:10]1([CH2:24][O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:14][C:13](=[O:15])[N:12]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:23])[CH2:11]1)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C1(CO)CC(=O)N(c2c(C)cccc2C)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(COS(C)(=O)=O)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
MsCl (105 μL, 1.35 mmol) was added to a cooled (0° C.) solution of 1-(2,6-dimethyl-phenyl)-3-hydroxymethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step a, 250 mg, 0.9 mmol) and Et3N (375 μL, 2.7 mmol) in THF (5 mL). The resulting reaction mixture was stirred overnight at room temperature. Water (10 mL) was added and extracted with EtOAc (3×25 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried (Na2SO4) and evaporated. The obtained crude product 1-(2,6-dimethyl-phenyl)-3-methanesulfonyloxymethyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester was used as such for the next step. LC-MS: Rt (retention time): 1.73 min, MS: (ES) m/z 356.3 (M+H+).
Reaction SMILES: [Si:1]([N:8]1[C@@H:11]([CH2:12]I)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Si:1]([N:8]1[C@@H:11]([CH2:12][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:10][C:9]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CI
Product: CC(C)(C)[Si](C)(C)N1C(=O)C[C@@H]1CN1CCCCC1
Yield: 71 %

Procedure:
1-(tert-butyldimethylsilyl)-4(R)-(iodomethyl)-azetidin-2-one (202 mg, 0.62 mmol) was heated at reflux in piperidine (5 mL) for 2 h. The solution was concentrated, dissolved in CH2Cl2 and washed with saturated NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc) to give 1-(tert-butyldimethylsilyl)-4(R)-(piperidin-1-ylmethyl)azetidin-2-one (116 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 3.70-3.63 (m, 1H), 3.16 (dd, J=15.3, 5.4 Hz, 1H), 2.70-2.61 (m, 2H), 2.45-2.26 (m, 5H), 1.60-1.53 (m, 4H), 1.46-1.38 (m, 2H), 0.96 (s, 9H), 0.24 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([NH:20][O:21]C4CCCCO4)=[O:19])=[CH:13][CH:14]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1>CO.Cl>[OH:21][NH:20][C:18]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][CH2:17][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH2:9]2)=[CH:14][CH:13]=1)=[O:19]
Reactant: Cc1ccc(C(=O)N2CCc3ccc(C(=O)NOC4CCCCO4)cc3C2)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(C(=O)N2CCc3ccc(C(=O)NO)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
A mixture of 70 mg 2-(4-methylbenzoyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-7-carboxamide in 6 ml methanol and 6 ml 0.1 N aqueous hydrochloric acid is stirred overnight at ambient temperature. Subsequently, the reaction mixture is evaporated. The residue is dissolved in a mixture of water and acetonitrile and lyophilized. The crude product is further purified by silica gel flash chromatography. 11 mg of the title compound are obtained as colorless solid. MH+=311.1