Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([NH:11][C@H:12]([C:31]([OH:33])=[O:32])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)=[O:10].C(=O)(O)[O-].[Na+].[C:39]([O:42][CH:43](Cl)[CH3:44])(=[O:41])[CH3:40].O>CN(C=O)C>[C:39]([O:42][CH:43]([O:32][C:31](=[O:33])[C@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:30])[N:22]([CH3:29])[C:23](=[O:28])[N:24]([CH3:27])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH:11][C:9]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8])=[O:10])[CH3:44])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)Cl
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(F)cccc3F)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.6 %

Procedure:
To a suspension of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine (0.743 mmol, 340 mg) and sodium bicarbonate (5.94 mmol, 499 mg) in DMF (3.0 mL) was added 1-chloroethyl acetate (5.94 mmol, 0.73 g) at room temperature. The mixture was stirred for 48 h at room temperature. Then, the reaction mixture was poured into water (50 mL) and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with brine solution (80 mL) and were dried over anhydrous sodium sulfate. Filtration of the drying agent and concentration of the filtrate gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to obtain 265 mg (66% yield) of N-[(2,6-difluorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester as an amorphous white solid. ES-HRMS m/e calcd for C27H27F2N3O7 (M+Na) 566.1709, found 566.1710.
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[K].[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29]Br)=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]>CN(C=O)C.O>[CH2:13]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[O:25][CH2:24][C:23]([CH2:29][NH2:5])=[CH:22]2)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCOc1ccc2c(c1)C=C(CBr)CO2
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCOc1ccc2c(c1)C=C(CN)CO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.25 g (6.75 mmol) of potassium phthalimide are added to a solution of 1.4 g (4.5 mmol) of the brominated compound obtained in Step D in 15 ml of DMF; the medium is then stirred overnight at ambient temperature and under argon. After evaporation of the solvent in vacuo, the residue obtained is taken up in water; the aqueous phase is then extracted with dichloromethane. The organic phase, dried over magnesium sulphate and then filtered, is concentrated in vacuo. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) allows access to the title phthalimide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:26](O)=[O:27])[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:70]([OH:76])([C:72]([F:75])([F:74])[F:73])=[O:71]>CN(C)C=O.CO>[F:73][C:72]([F:75])([F:74])[C:70]([OH:76])=[O:71].[CH2:29]([NH:36][C:26]([C:9]1[CH:10]=[C:11]2[CH:25]=[C:7]([CH:8]=1)[NH:6][C:5]1=[N:23][C:22](=[C:2]([Cl:1])[CH:3]=[N:4]1)[NH:21][C:20]1=[CH:24][C:16](=[CH:17][CH:18]=[CH:19]1)[S:15][CH2:14][CH2:13][O:12]2)=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Temperature: 20 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
A solution of 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9,13)]tetracosa-1(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylic acid (30 mg, 72 μmol) and benzylamine (12 μL, 0.11 mmol) in N,N-dimethylformamide (1 mL) was treated with N,N-diisopropylethylamine (50 μL, 0.29 mmol) followed by 0.5 M O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in N,N-dimethylformamide (0.19 mL, 94 μmol) and stirred at 20° C. for 16 h. The reaction mixture was diluted with methanol (4.9 mL) and TFA (0.1 mL) and the resultant suspension was filtered. The filtrate was purified by preparative LCMS to give the desired product (7 mg, 16%) as a solid. LCMS for C26H23ClN5O2S (M+H)+: m/z=503.9. 1H NMR (300 MHz, DMSO-d6): δ 9.66 (s, 1H), 8.91-8.88 (m, 2H), 8.18 (s, 1H), 7.96 (d, J=5.6 Hz, 2H), 7.37-7.21 (m, 9H), 6.94 (s, 1H), 4.41 (d, J=5.9 Hz, 2H), 4.16-4.11 (m, 2H), 3.28-3.23 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:11]=[CH:12]\[C:13]1[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C:6]1[CH2:20][CH:21]3[NH:26][CH:25]([C:5]2=1)[CH2:24][CH2:23][CH2:22]3>CC(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][C:13]1[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)[C:6]1[CH2:20][C@@H:21]3[NH:26][C@H:25]([C:5]2=1)[CH2:24][CH2:23][CH2:22]3
Reactant: Cc1ccc2c(c1)c1c(n2/C=C\c2ccc(C)nc2)CC2CCCC1N2
Agent: O=[Pt]=O
Solvent: CC(C)O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)C[C@H]2CCC[C@@H]1N2
Temperature: 65 °C

Procedure:
A suspension of 2-methyl-5-[(Z)-2-(6-methylpyridin-3-yl)vinyl]-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (750 mg, 2.18 mmol; from Example 118B) and platinum(IV) oxide (105 mg, 0.462 mmol; Aldrich) in 2-propanol (30 mL) was heated to 65° C. under hydrogen balloon atmosphere (1 atm) for 16 hours, then cooled to room temperature. The catalyst and solvent were removed, and the residue was purified by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, flow rate 40 mL/minute, 20 minutes) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, CDCl3) δ ppm 0.96-1.14 (m, J=18, 18, 9, 5 Hz, 1H), 1.25-1.40 (m, 2H), 1.60 (dd, J=13, 2 Hz, 1H), 1.75-1.96 (m, 2H), 2.03 (d, J=17 Hz, 1H), 2.39 (s, 3H), 2.42 (s, 3H), 2.87 (dd, J=17, 7 Hz, 1H), 3.00-3.21 (m, 2H), 3.43 (t, J=6 Hz, 1H), 4.20-4.42 (m, 3H), 6.92 (dd, J=8, 1 Hz, 1H), 7.09-7.15 (m, 2H), 7.20 (d, J=8 Hz, 1H), 7.36 (dd, J=8, 2 Hz, 1H), 7.88 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 346 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[O:29]=[C:27]1[NH:12][C:11]2[C:10]([C:13]([F:14])([F:15])[F:16])=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[NH:1]1
Reactant: COC(=O)c1ccc(C(F)(F)F)c(N)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(F)(F)F)c2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of methyl 2,3-diamino-4-(trifluoromethyl)benzoate (5.10 g, 0.022 mol) and diisopropylethylamine (6.26 g, 0.048 mol) in toluene (50 ml) was added a solution of triphosgene (2.58 g, 0.0087 mol) in toluene (20 ml) dropwise and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with 1N hydrochloric acid and extracted with ethyl acetate and tetrahydrofuran. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. A solution of 50% diisopropylether/n-hexane was added to the residue and white precipitates were filtered, washed with same solvent to give 5.00 g (0.019 mol 87%) of the title as a white powder
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[O:7][CH2:8][C:9](=[O:15])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH2:2]1.C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.C1(CN)CC1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][N:42]=2)[C:37]([CH:44]=O)=[CH:36]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:35]1[C:43]2=[N:42][CH:41]=[CH:40][CH:39]=[C:38]2[C:37]([CH:44]=[C:8]2[O:7][C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]2=[O:15])=[CH:36]1
Reactant: COC(=O)C1=C(NCC2CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: NCC1CC1
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Solvent: COC(=O)CC(=O)OC
Product: COC(=O)C1=C(NCC2CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 13.7 %

Procedure:
To a solution of methyl 2-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.4 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and cyclopropylmethylamine, and 7-azaindole-3-carboxaldehyde (0.21 g, 1.4 mmol) in ethanol (10 mL), L-proline (0.016 g, 0.14 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.065 g, y. 14%).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1)(=[O:6])[CH2:4][CH3:5].O>C(Cl)(Cl)Cl>[Br:1][CH:4]([CH3:5])[C:3]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][N:8]=1)=[O:6]
Reactant: BrBr
Reactant: CCC(=O)c1ccc(C(F)(F)F)cn1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(Br)C(=O)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Bromine (0.52 ml.) in chloroform (50 ml.) was added to solution of 2-propionyl 5-trifluoromethylpyridine (2.03 g.) in chloroform (20 ml.) over 1 hour under photoflood illumination. After addition was complete the reaction was stirred for 16 hours at room temperature. The reaction was then poured into water, and the organic phase was separated, washed with water, dried over magnesium sulphate and concentrated to dryness to give 2-(2-bromopropionyl)-5-trifluoromethylpyridine as an oil which was used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][O:6][CH2:7][C:8]1[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([NH2:20])[C:11]=2[N:21]=1>ClCCl.C(N(CC)CC)C>[NH2:20][C:12]1[C:11]2[N:21]=[C:8]([CH2:7][O:6][NH:5][C:1](=[O:3])[CH3:2])[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]=2[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1
Reactant: CC(C)Cn1c(CON)nc2c(N)nc3c(c21)CCCC3
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NOCc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3
Reaction time: 1 h
Yield: 26.1 %

Procedure:
A solution of acetyl chloride (0.232 mL, 3.27 mmol) in dichloromethane (10 mL) was added dropwise to a stirred solution of 2-[(aminooxy)methyl]-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 123, 860 mg, 2.97 mmol) and triethylamine (1.24 mL, 8.92 mmol) in dichloromethane (20 mL) at 0° C. After 1 hour, additional acetyl chloride (0.232 mL) in dichloromethane (10 mL) and triethylamine (1.0 mL) were added. The reaction mixture was stirred for an additional 30 minutes, then was concentrated under reduced pressure. The crude product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% 1 M NH3 in methanol/dichloromethane) followed by crystallization from acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to yield 257 mg of N-{[4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}acetamide as pale yellow crystals, mp 187-188° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=2)[NH2:9])=[N:4][N:3]=[N:2]1.C(N(CC)CC)C.[C:20](N1C=CN=C1)(N1C=CN=C1)=[S:21].Cl>O.CN(C)C=O.ClCCl>[N:9]([C:8]1[CH:7]=[C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)[CH:12]=[CH:11][CH:10]=1)=[C:20]=[S:21]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: S=C=Nc1cccc(-c2nnn[nH]2)c1
Temperature: 0 °C
Yield: 64 %

Procedure:
The crude 3-(1H-tetrazol-5-yl)aniline was mixed with dichloromethane (15 ml) and cooled to 0° C., and stirred with 2.8 ml (20 mmol) of triethylamine, 2.14 g (12 mmol) of 1,1′-thiocarbonyldiimidazole and N,N-dimethylformamide (5 mL) vigorously at 0° C. for 1 hour. Water (10 ml) was added, and concentrated hydrochloric acid was gradually added dropwise. The light brown solid precipitated at pH 6 to 7 was collected by filtration. Concentrated hydrochloric acid was gradually added dropwise, and the light brown solid precipitated at pH 5 was collected by filtration. The light brown solid was dried under reduced pressure to obtain the desired product (1.31 g, yield 64%, purity 86%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([C:23]1[N:27]=[C:26]([NH2:28])[O:25][N:24]=1)([CH3:22])[CH3:21]>>[NH2:28][C:26]1[O:25][N:24]=[C:23]([C:20]([NH:19][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:22])[CH3:21])[N:27]=1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)(N)c1noc(N)n1
Agent: Cl
Product: CC(C)(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)c1noc(N)n1

Procedure:
The title compound was synthesized in analogy to Example 6, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g) and 3-(1-amino-1-methyl-ethyl)-[1,2,4]oxadiazol-5-ylamine hydrochloride (1:1) (Example 57b) as starting materials, and isolated (57 mg, 75%) as off-white solid; LC-MS (UV peak area, ESI) 100%, 359.1825 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[N:13]=[CH:12][N:11]=2
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(NC4CCNCC4)ncnc32)cc1
Yield: 89 %

Procedure:
A solution of tert-butyl 4-{[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}piperidine-1-carboxylate (180 mg, 0.33 mmol) was stirred in dichloromethane (9 mL) and trifluoroacetic acid (4 mL) for 16 h. The reaction was concentrated in vacuo. The crude product was dissolved in ethyl acetate and washed with saturated NaHCO3. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with brine and dried with MgSO4. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 129 mg (88%) of 8-(2-chlorophenyl)-9-(4-chlorophenyl)-N-(piperidin-4-yl)-9H-purin-6-amine. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45 (qd, J=11.66, 3.81 Hz, 2 H) 2.10 (d, J=11.87 Hz, 2 H) 2.64-2.88 (m, 2 H) 3.10 (d, J=12.62 Hz, 2 H) 4.27 (br. s., 1 H) 5.80 (d, J=6.31 Hz, 1 H) 7.01-7.55 (m, 8 H) 8.37 (s, 1 H), [M+H]+ 439.6.
Reaction SMILES: [C:1]1([C:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[OH-:29].[K+].[K].Cl>C1C=CC=CC=1.CO>[C:1]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][O:29][C:1]([CH3:17])([CH3:14])[CH3:2])=[O:24])=[CH:27][CH:28]=2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: [OH-]
Reactant: COC(=O)c1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)cc1
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: CO
Solvent: c1ccccc1
Product: CC(C)(C)OOC(=O)c1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 142.9 %

Procedure:
4-[(1-Pyrenyl)carbonyl]benzoic acid, methyl ester (2.55 g; 7 mmol) was dissolved in 25 ml of benzene. A solution of 354 mg (6.4 mmol) of KOH in 5 ml MeOH was added, and the mixture boiled. Preciptation of the potassium salt occurred. The mixture was extracted with water to give a yellow water layer which was acidified with dilute HCl to give a light yellow precipitate. Filtration gave 1.73 g (5 mmol) of the 4-[(pyrenyl)carbonyl]benzoic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57](O)=[O:58])(=[O:46])=[O:45])[CH:38]=[CH:37]2.[N:60]1([CH2:66][C:67]2[CH:68]=[C:69]3[C:74](=[CH:75][CH:76]=2)[C@H:73]([NH2:77])[CH2:72][CH2:71][CH2:70]3)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57]([NH:77][C@H:73]1[C:74]3[C:69](=[CH:68][C:67]([CH2:66][N:60]4[CH2:61][CH2:62][CH2:63][CH2:64][CH2:65]4)=[CH:76][CH:75]=3)[CH2:70][CH2:71][CH2:72]1)=[O:58])(=[O:45])=[O:46])[CH:38]=[CH:37]2
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Reactant: N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)N[C@@H]3CCCc4cc(CN5CCCCC5)ccc43)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
DIPEA (2.5 eq.), HOAt (1.0 eq.) and EDCl (1.5 eq.) were added to a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)-acetic acid S2 (0.195 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the mixture was stirred for 15 min at RT. Then (R)-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydro-naphthalen-1-amine A6 (0.234 mmol, 1.2 eq.) in DCM (2 ml) was added at 0° C. and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and extracted with aqueous NaHCO3 solution, aqueous NH4Cl solution, water and saturated NaCl solution. The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (alox). Yield: 55%; m/z=627.4 [MH]+
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7](O)=[O:8])[CH2:5][CH2:4][N:3]1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1.[CH3:28][NH2:29]>>[CH3:28][NH:29][C:7]([CH:6]1[CH2:5][CH2:4][N:3]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[C:2]1=[O:1])=[O:8]
Reactant: O=C(O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O
Reactant: CN
Product: CNC(=O)C1CCN(c2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 6d) from (RS)-2-oxo-1-[4-(4-trifluoromethyl-benzyloxy)-phenyl]-pyrrolidine-3-carboxylic acid and methylamine. Yield: 6% of a colorless solid. MS: m/e=393.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:38]=[CH:37][C:22]([CH2:23][NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:30]=4)=[CH:37][CH:38]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc(NCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of methyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]benzyl}amino)phenyl]propanoate (100 mg, 0.20 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 1 M aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was poured into water, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated. The residue was purified by silica gel column chromatography (20%-80% ethyl acetate/hexane) to give the title compound (75 mg, yield 77%) as colorless crystals.
Reaction SMILES: II.C([Si](C)(C)[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([F:22])([F:21])[F:20])[NH:18][NH:17]2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.Cl.O1CCOCC1>CO.CCN(CC)CC>[F:22][C:19]([F:20])([F:21])[C:16]1([C:13]2[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=2)[N:17]=[N:18]1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C2(C(F)(F)F)NN2)cc1
Agent: Cl
Agent: II
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CO
Product: OCc1ccc(C2(C(F)(F)F)N=N2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.7 %

Procedure:
I2 (1.14 g, 4.5 mmol) was added to a MeOH (4 mL) solution of Et3N (1.2 mL) and 3-(4-((tert.-butyldimethylsilyloxy)methyl)phenyl)-3-(trifluoromethyl)-diaziridine (1.65 g, 5.00 mmol). The solution was stirred at rt (3 h). Aqueous citric acid 10% (50 mL) and NaS2O3 were added. The organic layer was extracted 3 times with ether (3×30 mL). The organic layers were combined, dried and concentrated in vacuum to obtain a yellow oil; 1H NMR (CDCl3): δ 0.09 (s, (CH3)2Si), 0.94 (s, CH3)3C), 4.74 (s, CH2), 7.15 (d, J=8.0 Hz, 2 C6H4), 7.35 (d, J=8.0 Hz, 2 C6H4). HCl in dioxane (4 M, 5 mL, 20 mmol) was added to a MeOH (10 mL) solution of the yellow residue. The solution was stirred at rt (3 h) and the volatiles were evaporated. The residue was purified by silica gel flash chromatography to obtain 840 mg (78%) of a yellow liquid: Rf=0.19 (1/9 EtOAc/hexanes); 1H NMR (CDCl3): δ 1.95-2.05 (br, OH), 4.70 (s, CH2), 7.18 (d, J=8.4 Hz, 2 C6H4), 7.38 (d, J=8.4 Hz, 2 C6H4); 13C NMR (CDCl3): δ 28.3 (q, J=40.4 Hz, C diazirine), 64.4 (CH2O), 122.1 (q, J=273.0 Hz, CF3), 126.7 (C6H2), 127.1 (C6H2), 128.3 (C6H2), 142.5 (C6H2).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[N:6]=1>CO.[Pd]>[CH3:1][C:2]1[N:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nnn(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1nnn(-c2ccc(N)cc2)n1
Reaction time: 2 h

Procedure:
5-Methyl-2-(4-nitrophenyl)-2H-tetrazole (200 mg, 0.975 mmol) was suspended in methanol (15 mL). The solution was degassed and purged with nitrogen 3 times before palladium on carbon (10% w/w, 51.9 mg, 0.049 mmol) was added. The mixture was degassed and purged with hydrogen 3 times and stirred under a hydrogen balloon for 2 hours. The reaction was diluted with acetone and passed through a plug of silica gel, which was washed thoroughly with acetone. The filtrated was concentrated to give the crude product 4-(5-methyl-2H-tetrazol-2-yl)aniline which was used as isolated.