Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[CH2:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]=2[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5]2[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:3]=[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[C:9](=[O:11])[CH2:8]1
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)CC(=O)c2c(Br)cn(-c3ccccn3)c2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC1(C)CC(=O)c2c(-c3ccccc3)cn(-c3ccccn3)c2C1
Yield: 61.2 %

Procedure:
A solution of 3-bromo-6,6-dimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydroindol-4-one (100 mg, 0.31 mmol), phenylboronic acid (153 mg, 1.25 mmol), tetrakis(triphenylphosphine)palladium (50 mg, 0.04 mmol) and Na2CO3 (197 mg, 1.9 mmol) in ethylene glycol dimethyl ether (10 mL) and water (4 mL) was heated at reflux for 8 h. The solvent was evaporated and the residue partitioned between DCM and aqueous K2CO3 (10% (w/v)). The organic layer was separated and the aqueous phase re-extracted with DCM (2×). The combined organic layers were washed with water, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with isohexane: EtOAc (9:1), to afford the title compound (60 mg, 61%) as a yellow solid. mp 160-162° C. Found: C, 78.23; H, 6.26; N, 8.57%. Calc. C21H20N2O.0.35(H2O): C, 78.16; H, 6.47; N, 8.68%. 1H NMR (360 MHz, CDCl3) δ 1.13 (6H,s), 2.45 (2H,s), 2.99 (2H,s), 7.17 (1H,s), 7.24-7.38 (5H,m), 7.67 (2H,d, J=7.2 Hz), 7.86 (1H,d of t, J=7.9 and 1.9 Hz), 8.56-8.61 (1H,m). MS (ES+) 317 (M+1).
Reaction SMILES: [Zn:1].[CH3:2][S:3][C:4]1[N:9]=[C:8]([C:10]2[S:14][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1.O>C1COCC1.O>[CH3:2][S:3][C:4]1[N:9]=[C:8]([C:10]2[S:14][C:13]([S:15]([Zn:1])(=[O:17])=[O:16])=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(-c2ccc(S(=O)(=O)Cl)s2)n1
Reactant: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: CSc1nccc(-c2ccc(S(=O)(=O)[Zn])s2)n1
Reaction time: 22 h
Yield: 236.8 %

Procedure:
Zinc dust (106.5 mg, 1.63 mmol) in THF/H2O (2:1, 7.5 mL) was sonicated 15 minutes and 5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl chloride (500 mg, 1.63 mmol) was added all at once as a solid. After 22 hours, the mixture was concentrated to ¼ volume and a precipitate formed. Water was added and the suspension was sonicated for 1 minute. The solids were collected by filtration, washed with water and dried in vacuo to afford bis-5-(2-Methylsulfanyl-pyrimidin-4-yl)-thiophene-2-sulfonyl Zinc as a light yellow solid (1.3 g, >100%). This material was used in the next step. 1H NMR (500 MHz, DMSO-d6) δ 2.52 (s, 3H), 7.15 (d, J=3.5 Hz, 1H), 7.59 (d, J=5.5 Hz, 1H), 7.88 (d, J=3.5 Hz, 1H), 8.54 (d, J=5.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][CH2:22][CH2:23][OH:24].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>CN(C=O)C>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:21][CH2:22][CH2:23][OH:24])=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCO
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCO)c3)nc12

Procedure:
Following the same reaction and purification procedure, the acid 14 (80 mg, 0.30 mmol) was reacted with 2-aminoethanol (CAS 141-43-5) (36 mg, 0.6 mmol), HATU (141 mg, 0.36 mmol) and DIPEA (0.26 mL, 1.5 mmol) in DMF (1 mL) at room temperature to provide 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-hydroxyethyl)benzamide 16. LC/MS (ESI+): m/z 309 (M+H). 1H NMR (400 MHz, DMSO) δ 8.76 (s, 1H), 8.64 (t, J=5.5 Hz, 1H), 8.60 (d, J=7.9 Hz, 1H), 8.51 (d, J=8.9 Hz, 1H), 8.43 (s, 1H), 8.17 (t, J=12.9 Hz, 1H), 8.07 (d, J=24.4 Hz, 2H), 7.98 (d, J=7.7 Hz, 1H), 7.68-7.56 (m, 1H), 4.76 (t, J=5.6 Hz, 1H), 3.57 (q, J=6.0 Hz, 2H), 3.41 (q, J=6.0 Hz, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CC1c1cccc(Cl)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 55.7 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(3-chloro-phenyl)-pyrrolidin-3-ylamine (4.47 g, 16.0 mmol) in THF (50 ml) was added a solution of K2CO3 (4.31 g, 31 mmol) in H2O (35 ml). After 10 minutes, ethyl chloroformate (2.97 ml, 31 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (62 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (50 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 2.68 g (57%) of the title compound as a colorless oil. ES-MS m/e: 301.2 (M+H+).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2N[CH2:14][CH2:13][CH2:12]3)[CH2:3]1.N1CC(OC2C=CC=C3C=2N(C(C2C=CC=CC=2)C2C=CC=CC=2)CC=C3)C1>>[ClH:1].[CH2:12]1[C:11]2[C:16](=[C:7]([O:6][CH:4]3[CH2:5][NH:2][CH2:3]3)[CH:8]=[CH:9][CH:10]=2)[CH2:14][CH2:13]1
Reactant: c1cc2c(c(OC3CNC3)c1)NCCC2
Agent: C1=Cc2cccc(OC3CNC3)c2N(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Product: c1cc2c(c(OC3CNC3)c1)CCC2

Procedure:
8-(3-Azetidinyloxy)-1,2,3,4-tetrahydroquinoline hydrochloride, mp>250° C. starting from 8-(3-Azetidinyloxy)-1-(diphenylmethyl)-quinoline.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1>O1CCCC1>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:31]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:32])[N:8]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(C)C2=O)c1
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 271°-273° C.
Reaction SMILES: Cl.[CH3:2][NH:3][OH:4].C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]([F:32])([F:31])[C:13]1[CH:14]=[C:15]([C:19]2[S:23][C:22]3[CH2:24][CH2:25][CH2:26]/[C:27](=[N:28]\[C:29]#[N:30])/[C:21]=3[CH:20]=2)[CH:16]=[CH:17][CH:18]=1>CO>[CH3:2][N:3]1[C:29]([NH2:30])=[N:28][C:27]2([C:21]3[CH:20]=[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:31])[F:32])[CH:14]=4)[S:23][C:22]=3[CH2:24][CH2:25][CH2:26]2)[O:4]1
Reactant: N#C/N=C1\CCCc2sc(-c3cccc(C(F)(F)F)c3)cc21
Reactant: CNO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN1OC2(CCCc3sc(-c4cccc(C(F)(F)F)c4)cc32)N=C1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.2 %

Procedure:
To a solution of methylhydroxylamine hydrochloride (23 mg, 0.28 mmol) in methanol (2 mL) was added potassium carbonate (44 mg, 0.32 mmol) followed by (E)-N-(2-(3-(trifluoromethyl)phenyl)-6,7-dihydrobenzo[b]thiophen-4(5H)-ylidene)cyanamide (50 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 1 hr. The mixture was concentrated in vacuo and the crude residue partitioned between dichloromethane and water. The product was extracted into dichloromethane (×3). The organic extracts were combined, dried (MgSO4) and concentrated under reduced pressure. The crude residue was purified using preparative HPLC to give the title compound as yellow solid (34.2 mg, 58%). (regioisomeric mix with 2′-methyl-2-(3-(trifluoromethyl)phenyl)-6,7-dihydro-2′H, 5H-spiro[benzo[b]thiophene-4,3′-[1,2,4]oxadiazol]-5′-amine). 1H NMR δ (ppm)(DMSO-d6): 7.87-7.80 (2H, m), 7.64-7.58 (2H, m), 7.34 (1H, s), 6.12 (2H, s), 2.94 (3H, s), 2.80-2.60 (2H, m), 1.93-1.80 (3H, m), 1.80-1.69 (1H, m). HPLC (Method a) Rt 8.05 (min) m/z 368 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]([CH3:14])[C:9](=[O:13])[CH:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC>C(Cl)Cl.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:7]1[CH2:10][C:9](=[O:13])[CH:8]1[CH3:14])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)C=[N+]=[N-]
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1C(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(3-Diazo-1-methyl-2-oxo-propyl)-carbamic acid tert-butyl ester (0.250 g, 1.17 mmol) was dissolved in anhydrous DCM (6 mL) and Et3N (1.18 mg, 0.012 mmol) was added. The reaction mixture was cooled to 0° C. and rhodium (II) acetate (0.010 g, 0.023 mmol) was added. The reaction mixture was stirred at 0° C. for 1 h then concentrated in vacuo to give 2-methyl-3-oxo-azetidine-1-carboxylic acid tert-butyl ester, which was used in the next step without further purification. TLC (eluting with 20% EtOAc/heptane) Rf=0.3.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylate (7.63 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M hexane solution, 59 ml) at 0° C. and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-trifluoromethylphenyl)-4-isoxazolylmethanol (6.29 g, yield 97%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give a colorless prism. melting point: 106–107° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:9](=[O:23])[NH:10][CH:11]2[CH2:15][CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([CH2:7][CH:8]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[C:9](=[O:23])[NH:10][CH:11]2[CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(=O)NC1CCNC1

Procedure:
A solution of 21.2 g (50 mmol) of [R-(R*,S*)]-[1-phenylmethyl-2-oxo-2-[(1-(phenylmethyl)-3-pyrrolidinyl)amino]ethyl]carbamic acid, 1,1-dimethylethyl ester in 200 ml of methanol was treated with 1.0 g of 20% palladium on carbon and shaken in a hydrogen atmosphere at pressures of 32.5-53.4 psi and temperatures of 23.0°-27.5° for 18 hours. The catalyst was removed by filtration and the solvent was removed in vacuo to give 16.3 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[I-:11].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][I:11])=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: COc1ccc(CCl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CI)cc1
Reaction time: 1.5 h

Procedure:
A solution of 1.7 ml (12.8 mmol) of 4-methoxybenzyl chloride (Fluka; Buchs/Switzerland) in 25 ml of acetone is stirred with 9.4 g (62.6 mmol) of sodium iodide at room temperature. Gas chromatography of the reaction mixture after 90 minutes indicates that the reaction is complete, and the reaction mixture is therefore poured onto ether and washed with 10% sodium thiosulfate solution and brine. Drying of the organic phase with Na2SO4 and concentration by evaporation yield the title compound; 1H-NMR (200 MHz, CD3OD: 3.78 (s, 3 H), 4.54 (s, 2 H), 6.8-6.95 and 7.2-7.4 (2m, each 2 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH2:10])=[N:6]1.[CH:12]1[C:25]2[CH:24]([C:26](Cl)=[O:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:17][C:16]=2[CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3](=[O:11])[CH2:4][N:5]1[N:9]=[N:8][C:7]([NH:10][C:26]([CH:24]2[C:25]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[C:23]2=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:27])=[N:6]1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: COC(=O)Cn1nnc(N)n1
Product: COC(=O)Cn1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 243-244° and MS: (neg. ions): m/e=364.0 (M+−H) was prepared in accordance with the general method of example 1 from (5-amino-tetrazol-2-yl)-acetic acid methyl ester and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: C(C1C=CC2C(=CC=C(C(C)C)C=2)C=1)(C)C.C([C:20]1[C:21](C(C)C)=[C:22]([CH:30]([CH3:32])[CH3:31])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)(C)C>>[CH:30]([C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:20][CH:21]=1)([CH3:32])[CH3:31]
Reactant: CC(C)c1cc2ccccc2c(C(C)C)c1C(C)C
Agent: CC(C)c1ccc2cc(C(C)C)ccc2c1
Product: CC(C)c1cccc2ccccc12

Procedure:
A process for the production of 2,6-diisopropylnaphthalene is disclosed wherein an isopropylation reaction mixture containing isopropylated naphthalenes is subjected to transalkylation with a triisopropylnaphthalene-containing mixture to obtain a mixture containing mono-, di- and tri-isopropylnaphthalenes which is then separated into a first fraction containing monisopropylnaphthalenes, a second fraction containing diisopropylnaphthalenes and a third fraction containing triisopropylnaphthalenes. The first and third fractions are recycled to the above system, while the second fraction is subjected to separation treatments for the recovery of 2,6-diisopropylnaphthalene. The second fraction from which 2,6-diisopropylnaphthalene has been removed is subjected to transalkylation with naphthalene to obtain a monoisopropylnaphthalene-rich mixture which is to be fed to the isopropylation step.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[N:23]=[CH:24][CH:25]=1>>[N:21]1[N:22]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:11]3[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=3[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2=[O:9])[N:23]=[CH:24][CH:25]=1
Reactant: O=Cc1cccc(-n2nccn2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cccc(-n2nccn2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with 3-(2H-1,2,3-triazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 407.09 g/mol.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[C:30]1([NH:36][C:37]2[CH:38]=[CH:39][C:40]3[N:41]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:42]4[C:47]([C:48]=3[CH:49]=2)=[CH:46][CH:45]=[CH:44][CH:43]=4)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:5]2[C:6]3[C:11]([C:12]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)=[C:13]4[C:4]=2[CH:3]=[C:2]([N:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:37]2[CH:38]=[CH:39][C:40]5[N:41]([C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)[C:42]6[C:47]([C:48]=5[CH:49]=2)=[CH:46][CH:45]=[CH:44][CH:43]=6)[CH:15]=[CH:14]4)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:24][CH:25]=1
Reactant: Fc1ccc(-c2c3ccccc3c(-c3ccc(F)cc3)c3cc(Br)ccc23)cc1
Reactant: c1ccc(Nc2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2c3ccccc3c(-c3ccc(F)cc3)c3cc(N(c4ccccc4)c4ccc5c(c4)c4ccccc4n5-c4ccccc4)ccc23)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 63.6 %

Procedure:
2.0 g (4.5 mmol) of 2-bromo-9,10-bis(4-fluorophenyl)anthracene, 1.7 g (4.9 mmol) of N,9-diphenyl-9H-carbazol-3-amine (PCA), 0.13 g (0.23 mmol) of bis(dibenzylideneacetone)palladium(0), and 1.1 g (11 mmol) of sodium tert-butoxide were put into a 100 mL three-neck flask, and the atmosphere of the flask was substituted with nitrogen. Thereafter, 30 mL of toluene and 0.45 g (0.23 mmol) of tri(tert-butyl)phosphine (10% hexane solution) were added to the mixture, and this reaction mixture was stirred for 6 hours at 80° C. After the reaction was completed, the reaction solution was washed with water, and the aqueous layer was extracted with ethyl acetate. The extracted solution was combined with the organic layer, and then dried with magnesium sulfate. After drying, this mixture was subjected to suction filtration, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent: toluene), and then concentrated. The obtained solid was recrystallized with a mixed solvent of chloroform and hexane, giving 2.0 g of 9,10-bis(4-fluorophenyl)-2-[N-phenyl-N-(9-phenyl-9H-carbazol-3-yl)amino]anthracene (abbreviation: 2PCAFPA) as yellow powder in 62% yield. By nuclear magnetic resonance measurement (NMR), this compound was determined to be 9,10-bis(4-fluorophenyl)-2-[N-phenyl-N-(9-phenyl-9H-carbazol-3-yl)amino]anthracene (abbreviation: 2PCAFPA).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=3)[N:6]2[CH:30]=1>CO.[Pd]>[OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[N:9][CH:8]=[C:7]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:19][CH2:18]3)[N:6]2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc(N3CCOCC3)c3nc(CO)cn23)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(N3CCOCC3)c3nc(CO)cn23)CC1

Procedure:
Compound 26a (390 mg, 0.93 mmol) in MeOH (250 mL) was hydrogenated over 10% Pd/C in a continuous-flow hydrogenation reactor. The solvents were removed and the residue was dissolved in DCM, dried over Na2SO4, filtered, and concentrated to obtain compound 26b. Mass Spectrum (LCMS, ESI pos.) Calcd. for C21H31N5O4: 418.2 (M+H). Found 418.3.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.CC1C=CC=CC=1N=C=S>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:21]1[CH2:20][C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:37])=[S:35])=[CH:12][CH:13]=3)[CH:18]=2)[C:22]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Agent: Cc1ccccc1N=C=S
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4C)cc3)ccc2C1=O

Procedure:
The compound of example 272 was prepared analogous to compound of example 256 by reaction of compound of example 223 with 2-methyl phenyl isothiocyanate. The compound of example 272 was used directly without isolation, for the preparation of compound of example 273.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH2:23])=[N:9]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([NH:23][C:24](=[O:26])[CH3:25])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: CS(=O)(=O)c1ccc(-c2cc(N)nn2-c2ccc(F)cc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazol-3-amine (0.7 g) and acetic anhydride (0.22 ml) in dichloromethane (15 ml) was stirred at ambient temperature for 3 hours, and concentrated. The residue was purified by column chromatography on silica gel (15 g) eluting with a mixture of toluene and ethyl acetate (2:1). The desired product (0.63 g) was recrystallized from ethanol to give pale brown crystals of N-{1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-pyrazolyl}acetamide (0.52 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([O:20]C)=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].CO>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][CH:9]([C@H:22]([CH3:30])[CH2:23][CH:24]([CH3:29])[CH2:25][CH2:26][CH:27]=[CH2:28])[C:10]([N:12]1[CH2:16][C@H:15]([OH:17])[CH2:14][C@H:13]1[C:18]([OH:20])=[O:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCC(C)C[C@@H](C)C(NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a solution of (2S,4R)-methyl 1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylate (2.2 g, 5.1 mmole) in THF/water (20 mL, 1:1) was added LiOH (650 mg, 15 mmole) followed by 5 mL of methanol at room temperature. The reaction mass was stirred at room temperature for overnight. The solvent was evaporated under reduced pressure and the residue was diluted with water and acidified with aqueous 1.5 N HCl solution. The aqueous solution was extracted with ethyl acetate (20 mL×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get desired product (2S,4R)-1-((3R)-2-((tert-butoxycarbonyl)amino)-3,5-dimethylnon-8-enoyl)-4-hydroxypyrrolidine-2-carboxylic acid (1.8 g, 85%) as white solid. MS: MS m/z 411.2 (M+−1).
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3]C1C=CC=CC=1.[NH2:13][CH2:14][C:15]([OH:17])=[O:16]>>[NH2:13][C@H:14]([C:15]([OH:17])=[O:16])[CH2:3][CH2:2][C:10](=[O:11])[OH:12]
Reactant: NCC(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
1.07 His: 1.00 Phe: 2.10 Gly: 2.03