Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([CH3:25])([CH3:24])[C:11]([NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([CH3:23])[CH:15]=2)=[O:12])=[O:8])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=[N:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH:57][CH2:58][CH2:59]CN1CCCCC1>CN(C=O)C>[CH3:25][C:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:8])([C:11](=[O:12])[NH:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:50]2[CH2:45][CH2:46][CH2:47][CH2:48][CH:49]2[CH2:44][CH2:59][CH2:58][OH:57])=[O:20])=[C:16]([CH3:23])[CH:15]=1)[CH3:24]
Reactant: Cc1cc(NC(=O)C(C)(C)NC(=O)c2ccc(Cl)s2)ccc1C(=O)O
Reactant: OCCCN1CCCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)C(C)(C)NC(=O)c2ccc(Cl)s2)ccc1C(=O)N1CCCCC1CCCO

Procedure:
200 μl of a 0.05 molar solution of 4-{2-[(5-chloro-thiophene-2-carbonyl)-amino]-2-methyl-propionylamino}-2-methyl-benzoic acid, which additionally contains 0.05 mol/l DIPEA, in DMF are combined with 100 μl of a 0.1-molar solution of TBTU in DMF on a microtitre plate and mixed for 10 mins on a shaker. Then 200 μl of a 0,05-molar solution of (3-hydroxy-prop-1-yl)-piperidine, which additionally contains 0.05 mol/l DIPEA, are pipetted in and again mixed in by shaking. After 16 h at ambient temperature the mixture is filtered through basic aluminium oxide and washed with DMF/methanol=9:1. Then it is evaporated down i. vac.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](O)[CH2:23][CH3:24])=[CH:18][CH:17]=1.C(=O)([O-])[O-:27].[K+].[K+]>C(#N)CCC>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][C:10]([CH2:11][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][OH:27])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CCC(O)c1ccc(O)cc1
Agent: [K+]
Solvent: CCCC#N
Product: OCCCc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Temperature: 25 °C

Procedure:
12.8 g (41.4 mmol) of 4-phenylbenzyl bromide, 6.94 g (45.6 mmol) of 4-hydroxy-phenylpropanol and 6.87 g (49.7 mmol) of potassium carbonate are stirred in 50 ml of butyronitrile at 120° C. for 6 hours. Cooling to room temperature is followed by removal of the inorganic salts by filtration with suction and concentration in vacuo. The crude product is purified by chromatography on silica gel 60 (mobile phase gradient cyclohexane-->cyclohexane/ethyl acetate 60:40). 4.90 g (37% of theory) of product are obtained.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].N1(O[C:15]2[N:20]=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:18]([C:29]([NH2:31])=[O:30])=[CH:17][N:16]=2)C2C=CC=CC=2N=N1.C(#N)C>O>[NH2:3][CH2:2][CH2:1][NH:4][C:15]1[N:20]=[C:19]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:18]([C:29]([NH2:31])=[O:30])=[CH:17][N:16]=1
Reactant: NCCN
Reactant: Cc1ccc(Nc2nc(On3nnc4ccccc43)ncc2C(N)=O)cc1
Solvent: CC#N
Solvent: O
Product: Cc1ccc(Nc2nc(NCCN)ncc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A 3.0 ml portion of ethylenediamine was added to a mixture of 1.0 g of 2-(benzotriazol-1-yloxy)-4-(4-methylanilino)pyrimidine-5-carboxamide and 30 ml of acetonitrile, followed by stirring at room temperature for 1 hour and 40 minutes. Water was added to the reaction mixture, followed by extraction with a chloroform-isopropanol mixed solution. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure and then the thus obtained residue was purified by silica gel column chromatography (eluting solvent; chloroform:methanol:aqueous ammonia) . By recrystallizing the thus obtained colorless solid from an ethyl acetate-ethanol mixed solvent, 471 mg of 2-(2-aminoethylamino)-4-(4-methylanilino)pyrimidine-5-carboxamide was obtained (colorless crystals).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17].C(N(CC)C(C)C)(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[C:14]([CH3:24])=[C:15]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:16]([O:18][CH3:19])=[O:17])=[O:9]
Reactant: COC(=O)c1ccc(C)c(N)c1C
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(Br)ccc2F)c1C
Reaction time: 0.17 h
Yield: 51.9 %

Procedure:
To a solution of 5-bromo-2-fluoro-benzoic acid (500 mg, 2.28 mmol) in CH2Cl2 (15 mL) at 0° C. are added methyl 3-amino-2,4-dimethylbenzoate (409 mg, 2.28 mmol, see preparation 10) and N,N-diisopropylethylamine (737.6 mg, 5.71 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 1.74 g, 2.74 mmol) is added via syringe and stirred at 50° C. After 16 hours, the solvent is removed under reduced pressure and the residue is triturated with MeOH to give the title compound as a white solid (450 mg, 51.8%). Mass spectrum (m/z): 380.2 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10](C3CCCCO3)[CH:9]=[N:8][C:7]=2[N:6]([CH2:20][CH2:21][CH3:22])[C:5]1=[O:23])[CH2:2][CH3:3].[Li]CCCC.O[CH2:30][C:31]1([CH2:38][OH:39])[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]1.C1C[O:43][CH2:42][CH2:41]1>>[O:23]=[C:5]1[N:6]([CH2:20][CH2:21][CH3:22])[C:7]2[N:8]=[C:9]([C:34]34[CH2:33][CH2:32][C:31]([CH2:38][O:39][C:42](=[O:43])[CH3:41])([CH2:36][CH2:35]3)[CH2:30][O:37]4)[NH:10][C:11]=2[C:12](=[O:13])[N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: C1CCOC1
Reactant: CCCn1c(=O)c2c(ncn2C2CCCCO2)n(CCC)c1=O
Reactant: O=C1CCC(CO)(CO)CC1
Agent: [Li]CCCC
Product: CCCn1c(=O)c2[nH]c(C34CCC(COC(C)=O)(CC3)CO4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-Dipropyl-7-(tetrahydro-pyran-2-yl)-3,7-dihydro-purine-2,6-dione (5.30 g, 16.5 mmol) was dissolved in anhydrous THF (250 ml) and cooled to −78° C. nBuLi (2.5 M in hexanes, 6.60 ml, 1 eq) was added, followed by the ditosylate derivative of 4,4-bis-hydroxymethyl-cyclohexanone (7.7 g, 1 eq) and the reaction mixture was slowly warmed to RT and stirred at RT overnight. The next day, the reaction was quenched with sat'd. aq. NH4Cl. The reaction was diluted with water and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure. Purification by chromatography (2:1 hex/EtOAc) afforded 10.4 g of the ditoylate xanthine derivative.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14](=[O:39])[CH:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])C(OC(C)(C)C)=O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].FC(F)(F)C(O)=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14](=[O:39])[CH2:15][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: CCCCCCCCCCCCCCCCC(C(=O)OC(C)(C)C)C(=O)c1ccc(C(=O)OC(C)C)c(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCC(=O)c1ccc(C(=O)OC(C)C)c(Cl)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.9 %

Procedure:
335 mg of product from Example 9 was dissolved in 10 ml of methylene chloride and 10 ml of trifluroacetic acid was added. The reaction mixture was stirred at room temperature for 1.5 hours and added to 20 ml of water. The organic layer was separated and dried over sodium sulfate. The solvent was removed using a rotary evaporator to give 270 mg of the titled product.
Reaction SMILES: [OH-].[NH4+:2].[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=O)[CH2:5][CH2:4]1>CO>[O:3]1[CH2:8][CH2:7][CH:6]([C:9]([NH2:2])=[O:11])[CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: COC(=O)C1CCOCC1
Agent: [OH-]
Solvent: CO
Product: NC(=O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ammonium hydroxide (1 L) was added to a solution of methyl tetrahydro-2H-pyran-4-carboxylate (20 mL, 150 mmol) in methanol (500 mL), and the reaction was stirred overnight at ambient temperature. Additional ammonium hydroxide (500 mL) was added, and the reaction was stirred for four additional days. The methanol was removed under reduced pressure. Solid sodium chloride was added to the aqueous layer, which was extracted with chloroform (3×150 mL). The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 11.4 g of tetrahydro-2H-pyran-4-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1.[B-](F)(F)(F)[F:19].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[F:19][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: F[B-](F)(F)F
Reactant: COc1ccc([N+](=O)[O-])cc1-c1ccnn1C
Agent: *CC(*)C
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: COc1ccc([N+](=O)[O-])cc1-c1c(F)cnn1C
Temperature: 80 °C
Yield: 33.3 %

Procedure:
5-(2-Methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (300.0 mg, 1.29 mmol) was dissolved in ACN (15 ml) in a polypropylene 20 mL scintillation vial. To this solution, Selectfluor (913.9 mg, 2.58 mmol) was added and the mixture was degassed with argon and heated to 80° C. for 6 hours. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL EtOAc and 30 mL 3N HCl. The organic layer was separated and the aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was then purified by flash chromatography (Biotage SiO2, Hexanes (0.01% TEA)/EtOAc gradient elution) to afford 108 mg (33%) of 4-fluoro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole as a white solid. LCMS m/z (%)=252 (M+H, 100). 1H NMR (400 MHz, CDCl3) δ: 8.39 (d, J=9.2 Hz, 1H), 8.22 (s, 1H), 7.44 (d, JH,F=4.4 Hz, 1H), 7.12 (d, J=9.2 Hz, 1H) 3.98 (s, 3H), 3.77 (s, 3H). 19F NMR (376 MHz, CDCl3) δ: −175.50 (d, JH,F=5.3 Hz, 1F).
Reaction SMILES: [CH:1]([C:4]1[C:5]([NH:17][C:18]([O:20]C(C)(C)C)=O)=[C:6]([NH:9][C:10](OC(C)(C)C)=[O:11])[S:7][CH:8]=1)([CH3:3])[CH3:2].C(OCC)(=O)C(OCC)=O>C(O)(=O)C>[CH:1]([C:4]1[C:5]2[NH:17][C:18](=[O:20])[C:10](=[O:11])[NH:9][C:6]=2[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(NC(=O)OC(C)(C)C)c1NC(=O)OC(C)(C)C
Solvent: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CC(C)c1csc2[nH]c(=O)c(=O)[nH]c12

Procedure:
A mixture of di-t-butyl 4-isopropylthiophene-2,3-dicarbamate (1.42 g, 3.98 mmol), diethyl oxalate (25 ml, 183 mmol) and glacial acetic acid (25 ml) was refluxed for 2 h. The reaction mixture was cooled on ice for 2 h and the precipitate was filtered off, washed twice with water and finally with ether. Yield 580 mg (69%) of the title compound. M.p.>250° C. 1H-NMR (DMSO-D6, δ) 1.15 (d, 6H), 3.1 (m, 1H), 6.75 (s, 1H), 11.9 (br.s, 2H). MS (70 eV): m/z 210 (100%, g), 195 (97), 182 (42), 167 (52), 154 (12), 139 (29), 122 (13), 97 (19).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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>[CH3:24][N:25]1[CH:29]=[C:28]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:27]=[N:26]1
Reactant: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of 7-[(R)-1-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (18.9 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.13 (d, J=6.6 Hz, 3H), 3.96 (s, 3H), 6.33 (q, J=6.6 Hz, 1H), 6.76 (d, J=2.3 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.63 (d, J=9.9 Hz, 1H), 7.85 (s, 1H), 7.93 (s, 1H), 8.08 (s, 1H), 8.13 (d, J=9.6 Hz, 1H). MS (ES+): m/z 377.11 (100) [MH+]. HPLC: tR=1.95 min (ZQ3, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.O.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.[CH2:24](O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[CH2:24]([O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OCc1ccccc1
Reactant: Nc1cccc(CC(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-amino-phenylacetic acid benzyl ester p-toluene sulphonic acid was prepared by adding 3-aminophenylacetic acid (10 g) and p-toluene sulphonic acid monohydrate (13.2 g) to benzyl alcohol (27.2 ml) in toluene (30 ml). The mixture was heated under reflux and the water formed collected in a Dean-Stark receiver. When all the water had been distilled off the mixture was allowed to cool to 25° C. before diluting with diethyl ether and placing in an ice-bath for 1 hr. The crystalline p-toluene sulphonate was filtered off and dried in a dissicator (23.5 g) NMR δ2.31(s)3H, 3.82(s)2H, 5.11(s)2H, 7.11(d)2H, 7.25-7.45(m)8H, 7.52(d)2H.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:24][NH:25][C:26]([C@@H:28]([NH:33][C:34]([C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1C(OCC1C=CC=CC=1)=O)=[O:35])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:27])([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:2].C(N(CC)CC)C.[C:58](Cl)(=[O:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1>C(O)C.Cl.ClCCl.[Pd]>[CH2:1]([O:3][P:4]([CH2:24][NH:25][C:26](=[O:27])[C@H:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:33][C:34](=[O:35])[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:58](=[O:65])[C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)([CH2:6][CH:7]([C:12](=[O:23])[NH:13][C@H:14]([C:19](=[O:22])[NH:20][CH3:21])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H]1CCCN1C(=O)c1ccccc1)CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC
Temperature: 0 °C
Reaction time: 16 h

Procedure:
0.36 g of benzyl(S)-2-[[(S)-1-[[[ethoxy[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinyl]methyl]carbamoyl]-3-methylbutyl]carbamoyl]-1-pyrrolidinecarboxylate was dissolved in 5 ml of ethanol containing 0.5 ml of 1 M hydrochloric acid. The solution was hydrogenated over 5% palladium-on-charcoal for 2 hours. After filtration and evaporation of the filtrate, the residue was re-evaporated with toluene until a white solid was obtained. This solid was dissolved in 6 ml of dichloromethane. The solution was cooled to 0° C. and treated with 0.15 ml of triethylamine and 0.064 ml of benzoyl chloride. The mixture was stirred at room temperature for 16 hours and the solvent was then removed by evaporation. The residue was dissolved in ethyl acetate. The mixture was filtered and the filtrate was evaporated to give a pale yellow gum. Chromatography on silica gel using 3% ethanol in chloroform for the elution followed by evaporation yielded 0.32 g of [[ [N-(1-benzoyl-L-prolyl)-L-leucyl]amino]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.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.[NH2:44][C:45]1[CH:46]=[CH:47][C:48]2[CH2:54][CH2:53][CH2:52][C:51]([C:55]([O:57][CH3:58])=[O:56])=[C:50]([CH3:59])[C:49]=2[CH:60]=1>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:44][C:45]2[CH:46]=[CH:47][C:48]3[CH2:54][CH2:53][CH2:52][C:51]([C:55]([O:57][CH3:58])=[O:56])=[C:50]([CH3:59])[C:49]=3[CH:60]=2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: COC(=O)C1=C(C)c2cc(N)ccc2CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1=C(C)c2cc(NC(=O)c3ccc(Cl)cn3)ccc2CCC1
Reaction time: 0.17 h
Yield: 83 %

Procedure:
To a solution of 5-chloropicolinic acid (354 mg, 2.248 mmol) in dichloromethane (5 mL) was added HATU (940 mg, 2.473 mmol) and DIPEA (0.589 mL, 3.37 mmol). After stirring for 10 min, methyl 2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate from preparation J, step J1 (260 mg, 1.124 mmol) was added. The mixture was stirred at rt for 4 h. Ethyl acetate (100 mL) was added and the organic layer was washed with water. After concentration of the organic layer, the residue was purified using silica gel column chromatography (hexanes-100% EtOAc) to give methyl 2-(5-chloropicolinamido)-9-methyl-6,7-dihydro-5H-benzo[7]annulene-8-carboxylate (345 mg, 0.930 mmol, 83% yield). LCMS (M+H)+=371.3. 1H NMR (400 MHz, chloroform-d) δ 9.84 (s, 1H), 8.56 (dd, J=2.4, 0.6 Hz, 1H), 8.25 (dd, J=8.4, 0.6 Hz, 1H), 7.88 (dd, J=8.4, 2.4 Hz, 1H), 7.73 (d, J=2.3 Hz, 1H), 7.63 (dd, J=8.0, 2.3 Hz, 1H), 7.20 (d, J=8.3 Hz, 1H), 3.82 (s, 3H), 2.55 (t, J=6.5 Hz, 2H), 2.44 (s, 3H), 2.18-2.08 (m, 4H).
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[N:12][N:13]=[C:14]2[CH2:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29])C1C=CC=CC=1.[ClH:30]>C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:28].[ClH:30].[Cl:29][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:28])[C:22]=1[CH2:21][C:14]1[C:15]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[C:10]=2[CH:11]=[N:12][N:13]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
5-Benzyloxy-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (4.3 g, 10.08 mmoles), prepared as described in example 71, in glacial acetic acid and 7% HCl was put in a flask under stirring at room temperature for ½ hour, then at 60° C. for 1 hour. The mixture was brought to dryness, taken up more times in toluene to give a solid which was triturated in acetone and dried to give 4.04 g of the title compound (yield: 98%).
Reaction SMILES: [CH:1]1([CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14](Cl)=[CH:15][CH:16]=2)=[O:10])[CH2:4][CH2:3][CH2:2]1.[N:18]1([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH:1]1([CH2:5][CH2:6][CH2:7][NH:8][C:9]([C:11]2[N:12]=[N:13][C:14]([N:21]3[CH2:22][CH2:23][N:18]([C:24](=[O:25])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:20]3)=[CH:15][CH:16]=2)=[O:10])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(NCCCC1CCC1)c1ccc(Cl)nn1
Product: O=C(NCCCC1CCC1)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 15, making variations only as required to use 6-chloropyridazine-3-carboxylic acid (3-cyclobutylpropyl)amide in place of 6-chloropyridazine-3-carboxylic acid (2-cyclopropyl-2-hydroxyethyl)amide to react with piperazin-1-yl-(2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (28% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.85, 7.73, 7.57, 7.34, 6.99, 4.05, 3.89-3.65, 3.45, 3.33, 2.27, 1.99, 1.76, 1.58-1.39. 13C NMR (75 MHz, CDCl3) δ 167.6, 162.8, 159.9, 145.4, 134.2, 132.4, 129.5, 127.2, 126.9, 126.7, 112.7, 46.4, 44.6, 44.5, 41.2, 39.4, 35.7, 34.1, 28.3, 27.2, 18.4. MS (ES+) m/z 475.9 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([C:7]([C:9]2[N:13]([CH3:14])[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=2[CH3:21])=[O:8])=[CH:5][CH:4]=1)#[N:2].C(I)CCCCC>>[CH2:15]([C:12]1[N:13]([CH3:14])[C:9]([C:7](=[O:8])[C:6]2[CH:22]=[CH:23][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[C:10]([CH3:21])[CH:11]=1)[CH3:16].[CH2:12]([CH2:15][C:16]([O-:18])=[O:17])[CH2:11][CH2:10][CH2:9][CH2:7][CH3:6]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc(C#N)cc2)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc(C#N)cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 93), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-cyanobenzoyl)-1,4-dimethylpyrrole-2-(-n-hexyl)-acetate.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]2[O:14][CH:13]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12](=[O:22])[NH:11][C:10]=2[CH:23]=1.[ClH:24].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>O.[Cu]=O.CC(C)=O>[CH2:15]([CH:13]1[C:12](=[O:22])[NH:11][C:10]2[CH:23]=[C:6]([CH2:27][CH:26]([Cl:24])[C:25]([O:29][CH3:30])=[O:28])[CH:7]=[CH:8][C:9]=2[O:14]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)C(Cc1ccccc1)O2
Reactant: C=CC(=O)OC
Reactant: Cl
Agent: O=[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Cl)Cc1ccc2c(c1)NC(=O)C(Cc1ccccc1)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of 1.3 g of sodium nitrite in 3 ml of water is added to a mixture of 4.8 g of 6-amino-2-benzyl-3-oxo-1,4-benzoxazine, 3 ml of conc. hydrochloric acid and 60 ml of acetone. After the mixture is stirred at room temperature for 30 minutes, 10.6 ml of methyl acrylate are added thereto, and 500 mg of copper oxide (I) are added gradually at a temperature of 35° to 40° C. After stirring for 30 minutes, the mixture is poured into water and extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1) to give 4.95 g of crude methyl 3-(2-benzyl-3-oxo-1,4-benzoxazin-6-yl)-2-chloropropionate.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:22][CH2:23]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.[Cl-].C[Al+]C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH2:35]>C1(C)C=CC=CC=1>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:35]([CH2:34][C:33]3[CH:36]=[CH:37][CH:38]=[C:31]([Cl:30])[CH:32]=3)[CH2:23][CH2:22]2)[CH2:7][CH2:8]1)(=[O:13])=[O:14]
Reactant: NCc1cccc(Cl)c1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C1N(Cc2cccc(Cl)c2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2

Procedure:
This material was prepared in analogy to example 1 step D) from 1-(2-chloro-benzenesulfonyl)-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester, dimethylaluminium chloride in toluene and 3-chloro-benzylamine. MS (ESI): 453.1 (MH+).