Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1CCCC(CC(O)=O)C1.[F:12][C:13]1[CH:14]=[C:15]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:16][C@H:17]([NH:31][C:32](=[O:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH:37](CCC)[C:36](=[O:43])[CH2:35]1)[C@H:18]([OH:30])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=1>>[F:12][C:13]1[CH:14]=[C:15]([CH:45]=[C:46]([F:48])[CH:47]=1)[CH2:16][C@H:17]([NH:31][C:32](=[O:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][C:36](=[O:43])[CH2:35]1)[C@H:18]([OH:30])[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][CH3:29])[CH:23]=1
Reactant: CCCC1CCC(CC(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)CC1=O
Agent: O=C(O)CC1CCCC(=O)C1
Product: CCc1cccc(CNC[C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)CC2CCCC(=O)C2)c1
Yield: 23 %

Procedure:
Step 3 N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-oxocyclohexyl)acetamide was prepared in 23% yield from (3-Oxo-cyclohexyl)-acetic acid by the method described for the synthesis of N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(3-oxo-4-propylcyclohexyl)acetamide (EXAMPLE SP-297.)
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][CH:33]=1)CCC>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[S:30]1[CH:31]=[CH:32][CH:33]=[C:29]1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2cccs2)cc1)N1Cc2cccn2Cc2ccccc21
Yield: 81.8 %

Procedure:
A mixture of 1.64 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.9 g of 2-tri-n-butylstannyl thiophene and 200 mg of tetrakis(triphenylphosphine)palladium(O) in 200 ml of toluene is refluxed under nitrogen for 16 hours. The reaction mixture is evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with 5:1 hexane:ethyl acetate to give 1.2 g of the desired product as a solid. Mass spectrum: M+H:371.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[C:21](=[O:28])[CH:22]=[C:23]([CH2:26][OH:27])[O:24][CH:25]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[CH3:38][S:39]([O:27][CH2:26][C:23]1[O:24][CH:25]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[C:21](=[O:28])[CH:22]=1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1cc(CO)occ1OCCCCCOc1ccnc2cc(C(F)(F)F)ccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(=O)c(OCCCCCOc2ccnc3cc(C(F)(F)F)ccc23)co1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of 5-(5-(7-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-2-(hydroxymethyl)-4H-pyran-4-one 12 (240 mg, 0.57 mmol) in CH2Cl2 (15 mL) was added at 0° C. triethylamine (96 μL, 0.68 mmol), methanesulfonyl chloride (53 μL, 0.68 mmol). The solution was stirred at RT for 1.5 h. Dichloromethane (50 mL) was added and the solution was washed with water (3×100 mL), dried over MgSO4, filtered and evaporated. (5-(5-(7-(trifluoromethyl)quinolin-4-yloxy)pentyloxy)-4-oxo-4H-pyran-2-yl)methyl methanesulfonate 17 was obtained (260 mg, 91% yield) as a crude yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[N:8][CH:9]=1)([O-])=O>C(O)(=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][S:10][C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(SCc2cccnc2)nc1
Solvent: CC(=O)O
Product: Nc1ccc(SCc2cccnc2)nc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 87.4 %

Procedure:
5-nitro-2-[(3-pyridinylmethyl)sulfanyl]pyridine (5.6 g) was dissolved in acetic acid (56 ml), reduced iron (16.8 g) was added to the mixture, and the mixture was stirred for 40 hours at room temperature. The mixture was filtered with Celite, and washed with ethyl acetate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 6-[(3-pyridinylmethyl)sulfanyl]-3-pyridinylamine (4.3 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[C:6]([O:10][C:11]([N:13]1[CH2:16][CH2:15][CH:14]1[C:17]([OH:19])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7].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(#N)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:17]([CH:14]1[CH2:15][CH2:16][N:13]1[C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])=[O:19])[CH3:2]
Reactant: CCNCC
Reactant: CC(C)(C)OC(=O)N1CCC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)C1CCN1C(=O)OC(C)(C)C
Yield: 64.6 %

Procedure:
A solution of diethylamine (0.453 g), azetidine-1,2-dicarboxylic acid-1-t-butyl ester (Intermediate 209, 0.891 g), HATU (2.53 g) and DIPEA (1.72 g) in acetonitrile (20 ml) was stirred at room temperature under argon for 4 hours. The mixture was evaporated to dryness and ethyl acetate was added to the residue. The solution was washed with 1M NaOH, brine and water then dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-4% to give t-butyl 2-diethylcarbamoylazetidine-1-carboxylate (0.733 g) as light brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O>CN(C=O)C.O>[F:24][C:23]([F:26])([F:25])[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxyl benzaldehyde (1.1 g, 8.7 mmol) and Cs2CO3 (4.3 g, 13.1 mmol) in DMF (16 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.5 mL, 10.5 mmol). The reaction mixture was stirred at rt for 1 h and then diluted with H2O, followed by extraction with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The NMR of the crude product obtained (1.8 g, 100%) was clean. 1H NMR (CDCl3, 400 MHz) δ 9.93 (s, 1H), 7.91-7.87 (m, 2H), 7.09-7.05 (m, 2H), 4.45 (q, J=8.0 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.Cl.[OH:9][CH:10]([C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[O:25][CH3:26])[C:11](=[NH:15])[O:12]CC.[O:27]1CCC[CH2:28]1>C1(C)C=CC=CC=1>[CH3:26][O:25][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:16]=1[CH:10]1[O:9][C:28](=[O:27])[NH:12][C:11]1=[O:15]
Reactant: CCOC(=N)C(O)c1c(OC)cccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cccc([N+](=O)[O-])c1C1OC(=O)NC1=O

Procedure:
By the procedure of Example 27, but using 3 rather than 3.2 equivalents of triethylamine, ethyl 1-hydroxy-1-(2-methoxy-6-nitrophenyl)methanecarboximidate hydrochloride (12 g., 0.041 moles) in 400 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(2-methoxy-6-nitrophenyl)oxazolidine-2,4-dione (8.8 g., 86%; m.p. 181°-183° C.; m/e 252).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].[H-].[Na+].[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=1)=[CH2:19].C(O)C>CN(C)C=O>[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].[C:1]([O:7][CH2:19][CH2:18][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=1)(=[O:6])[CH2:2][C:3]([O-:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: C=Cc1ccc(C(=O)CCCCCCC)cc1
Agent: CCC(CC)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
4′-(2-Iodoethyl)octanophenone prepared (5 g) in the step D-3 was dissolved in anhydrous N,N-dimethylformamide (15 ml) to obtain 4′-(2-iodoethyl)octanophenone solution. Diethyl acetamide malonate (9.09 g) was dissolved in anhydrous N,N-dimethylformamide (30 ml) to obtain a solution to which 60% sodium hydride oil dispersion (1.23 g) was added with cooling. The solution was stirred under atmosphere of nitrogen for 1 hour. 4′-(2-Iodoethyl)octanophenone solution was added to the solution, and the solution was stirred under atmosphere of nitrogen at 60° C. for 2 hours. The reaction solution was poured into ice water, and extracted with ether, and washed with saturated saline solution. The extracted solution was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1:0→3:1) as an eluate to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (3.2 g) and 4′-vinyl octanophenone (1.5 g) in the form of colorless crystal, respectively. The diethyl acetamide malonate (4.25 g) was dissolved in anhydrous N,N-dimethylformamide (30 ml) to obtain a solution, to which 60% sodium hydride oil dispersion (574 mg) was added. The solution was stirred under atmosphere of nitrogen at room temperature for 30 minutes. 4′-Vinyl octanophenone (1.5 g) and anhydrous ethanol (7.5 ml) were added to the solution, and the solution was stirred under atmosphere of nitrogen at 60° C. for 6 hours, and the solution was stirred at room temperature for 2 days. The reaction solution was poured into ice water, extracted with ether, and washed with saturated saline solution. The extracted solution was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography using hexane-ethyl acetate (1:0→4:1) as an eluate to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (2.29 g) in the form of colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2ccccc2C1c1ccc(Cl)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(C2NCCc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a round-bottomed flask was added crude benzyl 1-(6-chloropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (170 mg, 449 μmol), CH2Cl2 (10 mL) and TFA (10 mL). The reaction was allowed to stir at RT. After 3 days, LC-MS shows little progress. The reaction was concentrated in vacuo to remove CH2Cl2 and the resulting solution allowed to stir for another 3 days, then cautiously poured into 10% Na2CO3 and extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini® column (5 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with an linear gradient of 10% to 100% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min to give crude 1-(6-chloropyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline as a white solid. The crude solid was carried into the next step. MS (ESI pos. ion) m/z: 245 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=3[CH3:21])[C:15]([NH2:17])=[O:16])=[CH:9][CH:10]=2)[CH:5]=[N:4][N:3]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+].[NH:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43]>CN(C=O)C.[Cu]I>[CH3:21][C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([N:38]1[CH2:42][CH2:41][CH2:40][C:39]1=[O:43])=[N:3][N:4]=[CH:5]2
Reactant: Cc1ccc(C(N)=O)cc1-c1ccc2c(Cl)nncc2c1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(C(N)=O)cc1-c1ccc2c(N3CCCC3=O)nncc2c1

Procedure:
In a microwave tube was placed 3-(1-chlorophthalazin-6-yl)-4-methylbenzamide (0.150 g, 0.50 mmol), copper (I) iodide (0.0048 g, 0.025 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.014 g, 0.10 mmol), cesium carbonate (0.34 g, 1.1 mmol) and pyrrolidin-2-one (0.077 mL, 1.0 mmol) in 2 mL of DMF. The mixture was heated at 150°-200° C. for 20 minutes in the microwave. After cooling, the reaction was filtered through Celite®. Water was added to the filtrate and the mixture was extracted with dichloromethane (3×). The organic layer was concentrated and the crude material purified by HPLC to give 4-methyl-3-(1-(2-oxopyrrolidin-1-yl)phthalazin-6-yl)benzamide as white solid. Found MS (ES+)=347 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[C:12](Cl)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[C:12]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NC1=NC(=O)C2=CC=NC2=N1

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and octadecanoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CCO>[CH:5]1([CH:11]2[CH2:12][CH2:13][N:14]([CH2:3][CH2:2][C:1]#[N:4])[CH2:15][CH2:16]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1CCC(C2CCNCC2)CC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN1CCC(C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.7 %

Procedure:
Acrylonitrile (4.16 mL, 63.1 mmol, 2.50 equiv) was-added at 0° C. to a solution of 4-cyclohexylpiperidine (4.20 g, 25.3 mmol, 1.00 equiv) in EtOH (50 mL) and the resulting solution was stirred for 1.5 hours at room temperature. The solvent was removed to give 5.11 g (92%) of white solid, which was characterized spectroscopically and used without purification for the next reaction.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[C:38]([CH:43]=[CH:44][N:45]=2)[C:39]([NH:41][CH3:42])=[O:40])=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:37]=[C:38]([CH:43]=[CH:44][N:45]=2)[C:39]([NH:41][CH3:42])=[O:40])=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CNC(=O)c1ccnc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)c1ccnc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 41.3 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 2-{4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenyl}-N-methylisonicotinamide (0.450 g) and pyridine hydrochloride (230 mg), the title compound (110 mg) was obtained as a colorless amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][C:6]=2[CH:15]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C(=O)(O)[O-].[Na+]>[CH2:13]([O:12][C:10]([C:8]1[S:9][C:5]2[CH:4]=[CH:3][C:2]([N:1]([CH2:7][C:6]3[CH:15]=[CH:2][CH:3]=[CH:4][CH:5]=3)[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:6]=2[CH:7]=1)=[O:11])[CH3:14]
Reactant: CCOC(=O)c1cc2cc(N)ccc2s1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ccc2s1
Reaction time: 8 h

Procedure:
Ethyl 5-aminobenzothiophene -2-carboxylate (74 mg, 0.344 mmol) was dissolved in 1 mL of anhydrous DMF and reacted with benzyl bromide (100 μL, 0.84 mmol) in the presence of potassium carbonate (97 mg, 0.70 mmol) at 80° C. under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with water and sat. sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure and the crude left under high vacuum overnight. It was used in the next step without further purification. MS (EI): cal'd 402 (MH+), exp 402 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH3:18])[C:13](OC)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH2:17][CH3:18])[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Solvent: Cc1ccccc1
Product: CC[C@@H](C=O)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To a solution of (S)-methyl 2-(((benzyloxy)carbonyl)amino)butanoate (2.0 g, 7.96 mmol) in toluene (50 mL) was added dropwise at −78° C. under argon DIBAL-H (1M in toluene) (15.9 mL, 15.9 mmol) over a period of 20 minutes and the reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was quenched at −78° C. with aqueous 1.5 M potassium sodium tartrate solution (20 mL), and was allowed to warm to room temperature. The reaction mixture was extracted with a solution of EtOAc and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (24 g SiO2) using EtOAc in hexane from 0% to 30% in order to give the title compound (1.18 g, 64%) as a colorless oil. LC-MS: [M+H] 222.2; Rt 1.01 min; (LCMS method 1). 1H NMR (400 MHz, CHCl3-cf): 9.61 (s, 1H), 7.27-7.43 (m, 5H), 5.39 (br s, 1H), 5.15 (m, 2H), 4.15 (q, 1H), 1.96-2.11 (m, 1H), 1.64-1.82 (m, 1H), 1.01-0.79 (m, 3H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]1=[S:14])([OH:3])=[O:2].[C:15](=O)(O)[O-].[Na+]>CO>[S:14]=[C:6]1[N:5]([CH2:4][C:1]([O:3][CH3:15])=[O:2])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7]1
Reactant: O=C(O)Cn1c(=S)sc2ccccc21
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cn1c(=S)sc2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a stirred solution containing 45.1 g (0.2 mol) of 3-(carboxymethyl) benzothiazoline-2-thione in 600 ml of methyl alcohol, 142.0 g (1.0 mol) of boron trifluoride ether complex was added in one portion. An exothermic reaction set in causing a temperature rise from 20° to 37° C. The stirred solution was heated at reflux for 24 hours and then cooled to 0° C. After cooling, 1400 ml of 10% aqueous sodium bicarbonate was slowly added (foaming observed) at 0°-10° C. until pH 8 was obtained. After stirring at 0°-10° C. for one hour, the solid was collected by filtration, washed with water until neutral to litmus and air-dried at 25°-30° C. The product, 2-thioxo-3(2H)-benzothiazoleacetic acid, methyl ester was obtained in 94% yield, m.p. 127°-128° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Br:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[N:38]3[N:45]=[C:46]([C:48]([OH:50])=O)[CH:47]=[C:37]3[N:36]=2)=[CH:31][CH:30]=1.[S:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[CH2:56][NH2:57].C(N(CC)CC)C>C1COCC1.C(OCC)C>[S:51]1[CH:55]=[CH:54][CH:53]=[C:52]1[CH2:56][NH:57][C:48]([C:46]1[CH:47]=[C:37]2[N:36]=[C:35]([C:32]3[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=3)[CH:40]=[C:39]([C:41]([F:44])([F:42])[F:43])[N:38]2[N:45]=1)=[O:50]
Reactant: NCc1cccs1
Reactant: O=C(O)c1cc2nc(-c3ccc(Br)cc3)cc(C(F)(F)F)n2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(NCc1cccs1)c1cc2nc(-c3ccc(Br)cc3)cc(C(F)(F)F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP) (0.144 g, 0.327 mmol) was added to a suspension of 5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.115 g, 0.298 mmol) and thiophene-2-methylamine (0.034 mL, 0.327 mmol) in THF (10 mL) containing triethylamine (0.124 mL, 0.893 mmol). The reaction mixture was stirred overnight at room temperature, diluted with ethyl ether (5 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL). The organic layer was collected, concentrated under reduced pressure and the crude product was purified by column chromatography to give 5-(4-bromo-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (thiophen-2-ylmethyl)-amide (0.105 g, 73%).
Reaction SMILES: C([O-])(=[O:3])C.[Pb+2].C([O-])(=O)C.[CH3:10][C:11]1[CH2:17][C:15](=[O:16])[CH2:14][C:13]([CH3:19])([CH3:18])[CH:12]=1.O=O>N1C=CC=CC=1>[O:3]=[C:12]1[C:13]([CH3:19])([CH3:18])[CH2:14][C:15](=[O:16])[CH:17]=[C:11]1[CH3:10]
Reactant: CC(=O)[O-]
Reactant: CC1=CC(C)(C)CC(=O)C1
Agent: O=O
Agent: [Pb+2]
Solvent: c1ccncc1
Product: CC1=CC(=O)CC(C)(C)C1=O

Procedure:
3,8 g. of lead acetate in 100 ml. of pyridine are treated with 69 g. of β-isophorone. The mixture is gassed with oxygen at 70° C. for 2 hours with intensive stirring and subsequently worked up by distillation. [b.p. 62°-64° C., 0,2 Torr]. The conversion of β-isophorone used amounts to 31 g. corresponding 45%. Ketoisophorone is obtained in a yield of 26 g. corresponding to 76%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:16][C:17]1([F:21])[CH2:20][NH:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][C:17]([F:21])([F:16])[CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CNC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC(F)(F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 959 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.4 g, 0.20 mmol), 3,3-difluoroazetidine hydrochloride (0.31 g, 0.24 mmol) and 4 Å molecular sieves (2.4 g) in DCE (10 mL). The reaction mixture was stirred for 3 h at room temperature. Sodium triacetoxyborohydride (0.85 g, 4.01 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The suspension was filtered through Celite and the filtrate was concentrated in vacuo to give 4-(3,3-Difluoroazetidin-1-yl)piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (0.53 g, 96%). 1H NMR (300 MHz, CDCl3): δ 3.94-3.90 (m, 2 H), 3.57 (t, J=11.9 Hz, 4 H), 2.96-2.81 (m, 2 H), 2.34-2.23 (m, 1 H), 1.71-1.58 (m, 2 H), 1.45 (s, 9 H), 1.35-1.21 (m, 2 H).