Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](C2C=CC(F)=CC=2)=C1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=[O:27]>>[C:1]([O:5][C:6]([NH:8][C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:10][OH:27])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc(F)cc2)c2ccccc21
Reactant: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)Nc1ccccc1CO
Yield: 79 %

Procedure:
1-(t-Butoxy)carbonyl-3-(4-fluorophenyl)indole (0.340 g) was freed from the protecting group with the use of trifluoroacetic acid and then treated as in the above Production Example 54 to give the title compound (0.184 g) as a pale yellow oil (yield: 79.0%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33].O>C(O)(C)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@@H:8]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:9]([OH:16])[CH2:10][N:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[S:41]([C:38]1[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=1)(=[O:42])=[O:43])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 62.5 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
7.5 g (22.3 mmol) of (1S,2R)-(1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butyl ester and 2.7 g (26.8 mmol, 1.2 equiv) of triethylamine are dissolved in 100 g of isopropanol and heated to 60-65° C. 5.41 g (24.5 mmol, 1.1 eq) p-nitrophenyl-sulfonyl chloride are added in several portions within 30 minutes. The reaction mixture is kept at 60° C. for another 30 minutes. 10 g of water are added and the suspension is stirred for an additional 30 minutes at 60° C. The mixture is cooled to 25° C. within 90 min and the product is filtered off, washed with a mixture of isopropanol/water (1:1 v/v) and dried under vacuum to yield 11.23 g (96.5%) of white (1S,2R)-{1-benzyl-2-hydroxy-3-[isobutyl-(4-nitro-benzenesulfonyl)-amino]-propyl}-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]([N:24](C)[C:25](=O)OC(C)(C)C)[CH3:23])=[CH:18][CH:17]=2)=[C:4]([O:33]C)[CH:3]=1.BrB(Br)Br>>[ClH:1].[Cl:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([C@@H:22]([NH:24][CH3:25])[CH3:23])=[CH:18][CH:17]=2)=[C:4]([OH:33])[CH:3]=1
Reactant: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)N(C)C(=O)OC(C)(C)C)cc1
Agent: BrB(Br)Br
Product: CN[C@@H](C)c1ccc(-c2c(O)cc(Cl)c3[nH]c(=O)c4sccc4c23)cc1
Product: Cl
Yield: 106.8 %

Procedure:
Following General Procedure F, (S)-tert-butyl 1-(4-(6-chloro-8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)ethyl(methyl)carbamate (40 mg, 0.08 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.48 mL, 0.48 mmol) to afford the desired product (18 mg, 60%) as a white solid: 1H NMR (500 MHz, MeOD) δ 7.72-7.60 (m, 3H), 7.49-7.39 (m, 2H), 7.30 (s, 1H), 6.03 (d, J=5.4 Hz, 1H), 4.49 (q, J=6.9 Hz, 1H), 2.73 (d, J=4.3 Hz, 3H), 1.80 (d, J=6.9 Hz, 3H); ESI MS m/z 385 [C20H17ClN2O2S+H]+; HPLC >99% (AUC), tR=13.60 min.
Reaction SMILES: [CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].[OH-].[Na+]>CN(C=O)C.C1COCC1>[CH3:1][C:2]1([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C(=O)c2c[nH]c3ncc(-c4cccc(N5CCNCC5)c4)nc23)CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2cccc(-c3cnc4[nH]cc(C(=O)C5(C)CCCCC5)c4n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 0° C. solution of (1-methyl-cyclohexyl)-[2-(3-piperazin-1-yl-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone (24 mg, 0.06 mmol) in DMF (1 ml) was treated with Acetic anhydride (0.01 ml, 0.06 mmol). The reaction mixture was removed from the ice bath and allowed to stir at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc/sat. NaHCO3. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a white solid which was filtered through a Buchner funnel and washed with Et2O and Hexanes to afford a yellow solid. The yellow solid was dissolved in THF (2 ml) and treated with 1N NaOH (0.05 ml, 0.05 mmol). After stirring at room temperature for 16 hours, the reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a light brown oil. The oil was triturated with Et2O providing 4 mg (15%) of 1-(4-{3-[7-(1-methyl-cyclohexanecarbonyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-phenyl}-piperazin-1-yl)-ethanone as a pale brown solid. M+H=446.
Reaction SMILES: [C:1]([C:3]1([OH:18])[C:14]([CH3:16])([CH3:15])[CH2:13][C:6]2([O:10][CH:9]([CH3:11])[CH:8]([CH3:12])[O:7]2)[CH:5]=[C:4]1[CH3:17])#[CH:2].ClCCl.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])(=O)=O>O>[C:1]([C:3]1([O:18][Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[C:14]([CH3:16])([CH3:15])[CH2:13][C:6]2([O:7][CH:8]([CH3:12])[CH:9]([CH3:11])[O:10]2)[CH:5]=[C:4]1[CH3:17])#[CH:2]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: C#CC1(O)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: O
Product: C#CC1(O[Si](CC)(CC)CC)C(C)=CC2(CC1(C)C)OC(C)C(C)O2
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Under argon, 8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-ol (500 mg, 1.99 mmol) was dissolved in a round-bottom flask in abs. dichloromethane (15 ml) and cooled to 0° C., and lutidine (0.58 ml, 4.99 mmol) and triethylsilyl trifluoromethanesulfonate (0.68 ml, 2.99 mmol) were added dropwise. The resulting reaction mixture was stirred at 0° C. for 1 h and at room temperature for a further hour, and water was added after the reaction had ended. The aqueous phase was repeatedly extracted thoroughly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. By final column chromatography purification of the resulting crude product (ethyl acetate/heptane gradient), [(8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)oxy](triethyl)silane (400 mg, 55% of theory) was obtained in the form of a colorless oil. 1H-NMR (400 MHz, CDCl3 δ, ppm) 5.30 (s, 1H), 4.20 (m, 1H), 3.58 (m, 1H), 2.48 (s, 1H), 2.02 (d, 1H), 1.86 (s, 3H), 1.79 (d, 1H), 1.22 (m, 3H), 1.14-0.93 (m, 9H), 0.75 (m, 6H), 0.53 (t, 9H). A multi-necked round-bottom flask which had been dried thoroughly by heating was flushed with argon and evacuated repeatedly, and zirconocene chloride hydride (311 mg, 1.21 mmol) and degassed abs. tetrahydrofuran (3 ml) were then added under a constant stream of argon. The reaction solution was cooled to 0° C., and a solution of [(8-ethynyl-2,3,7,9,9-pentamethyl-1,4-dioxaspiro[4.5]dec-6-en-8-yl)oxy](triethyl)silane in abs. tetrahydrofuran (2 ml) was added dropwise. The resulting reaction solution was stirred at room temperature for 1 h and its analysis by NMR spectroscopy showed complete conversion into the desired biscyclopentadienyldimethyl[(E)-2-{2,3,7,9,9-pentamethyl-8-[(triethylsilyl)oxy]-1,4-dioxaspiro[4.5]dec-6-en-8-yl}vinyl]zirconium. 1H-NMR (400 MHz, CDCl3 δ, ppm) 7.75 (m, 4H), 7.36 (m, 6H), 7.27 (d, 1H), 5.39 (d, 1H), 5.31 (s, 1H), 3.69 (m, 1H), 3.62 (m, 1H), 2.10-2.06 (m, 2H), 1.61 (s, 3H), 1.32-1.22 (m, 12H), 0.89 (m, 6H), 0.83 (t, 9H). The synthesis intermediate II.25 obtained in this manner was used in the subsequent reaction in question without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](#[N:13])[CH2:10][C:11]#[N:12].N1CCCCC1>C(O)CCC>[C:2]1([CH:1]=[C:10]([C:9]#[N:13])[C:11]#[N:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC#N
Reactant: O=Cc1ccccc1
Solvent: CCCCO
Solvent: C1CCNCC1
Product: N#CC(C#N)=Cc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Into a 50-mL round-bottom flask, was placed benzaldehyde (4 g, 37.69 mmol, 1.00 equiv), propanedinitrile (3.3 g, 49.95 mmol, 1.30 equiv), n-butanol (10 mL), piperidine (1 mL). The resulting solution was stirred for 16 h at 20° C. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with 1×33 mL of H2O/EtOH(10/1). The solids were collected by filtration. The solid was dried in an oven. This resulted in 4.2 g (69%) of 2-(phenylmethylidene)propanedinitrile as a yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.C(OC(=O)C=C(C1C=CC=C2C=1C(C#N)=[CH:38][NH:39]2)C1C=CC=CC=1)C>>[NH:18]1[C:19]2[C:15](=[CH:14][C:13]([C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:5][C:4]([NH:39][CH3:38])=[O:3])=[CH:21][CH:20]=2)[CH:16]=[N:17]1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]ncc2c1

Procedure:
3-(1H-Indazol-5-yl)-N-methyl 3-phenyl-acrylamide CCIV was prepared from 3-(1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1.[NH2-].[Na+].N.Cl[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1.O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([Cl:16])[C:12]([CH3:17])=[N:11]1
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1Cl
Reactant: CCOC(=O)CCl
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1cc(-n2nc(C)c(Cl)c2C)c(F)cc1Cl
Reaction time: 3 h
Yield: 93.9 %

Procedure:
1-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,5-dimethyl-4-chloropyrazole (27.5 g) was dissolved in tetrahydrofuran (200 ml), and to the resultant solution was added sodium amide (4.0 g). When the evolution of ammonia gas from the reaction mixture ceased, ethyl monochloroacetate (12.3 g) was added dropwise to the reaction mixture. After the completion of addition, the reaction mixture was heated under reflux, with stirring for further 3 hours. To the reaction mixture, after cooling, were added toluene and water to form two layers. The organic layer as separated was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (33.9 g) as a pale brown crystalline solid. Recrystallization of this solid from cyclohexane afforded a white crystalline solid. m.p. 101°-104° C.
Reaction SMILES: CSC.B.[Br:5][CH2:6][C:7]([C:9]1[N:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[S:12][CH:13]=1)=[O:8].C1(B2N3CCC[C@@H]3C(C3C=CC=CC=3)(C3C=CC=CC=3)O2)C=CC=CC=1>O1CCCC1>[Br:5][CH2:6][CH:7]([C:9]1[N:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[S:12][CH:13]=1)[OH:8]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: B
Agent: c1ccc(B2OC(c3ccccc3)(c3ccccc3)[C@H]3CCCN23)cc1
Solvent: C1CCOC1
Solvent: CSC
Product: OC(CBr)c1csc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Borane methyl sulfide complex (2M in THF, 50 mL, 100 mmol) and 4-bromoacetyl-2-trifluoromethylthiazole (20.15 g, 73.5 mmol) were added separately and simultaneously over one our to (R)-tetrahydro-1,3,3-triphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1.2 g, 3.53 mmol) in tetrahydrofuran (50 mL) at ambient temperature. After the reduction was complete the reaction mixture was cooled to 0° C. and quenched with methanol (dropwise addition of 115 mL) while maintaining the temperature at less than or equal to 13° C. The quenched reaction mixture was stirred at 5° to 10° C. for ten minutes and then at ambient temperature for 45 minutes. The solvents were removed in vacuo and the residue was dissolved in methylene chloride (180 mL), washed with pH 4 aqueous phosphate buffer (180 mL), water (180 mL) and dried (MgSO4). The solvent was removed in vacuo to afford 4-(2-bromo-1-hydroxyethyl)-2-trifluoromethylthiazole as an amber oil (20.14 g, 99%, 90% ee). 1NMR (300 MHz, CDCl3 ): δ 7.61 (s, 1H), 5.13 (dd, J=4 Hz, J=7 Hz, 1H), 3.91 (dd, J=4 Hz, J=10 Hz, 1H), 3.70 (dd, J=7 Hz, J=10 Hz, 1H), 2.88 (bs, 1H).
Reaction SMILES: [I-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li][CH2:23][CH2:24][CH2:25][CH3:26].[NH2:27][C:28]1[C:37]2[N:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:31]2[CH:38]=CC(C=O)=[CH:41][C:30]=2[N:29]=1>C1COCC1>[CH:25]([C:24]1[CH:23]=[CH:38][C:31]2=[C:32]3[C:37](=[C:28]([NH2:27])[N:29]=[C:30]2[CH:41]=1)[N:36]=[CH:35][CH:34]=[CH:33]3)=[CH2:26]
Reactant: Nc1nc2cc(C=O)ccc2c2cccnc12
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(c1)nc(N)c1ncccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl triphenyl phosphonium iodide (6.0 eq.) was added nBuLi (7.0 eq.) at −78° C. The reaction mixture was allowed to warm to 0° C. and stirred for 30 minutes (deep orange color). The reaction was again cooled down to −78° C. and 5-aminobenzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 87) (1.0 eq.) in THF was introduced dropwised to the reaction. The reaction was allowed to warm to ambient temperature overnight. The reaction was quenched by saturated NH4Cl and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% EtOAc/Hexanes to give 8-vinylbenzo[f][1,7]naphthyridin-5-amine as a white solid: 1H NMR (acetone-d6): 1H NMR (acetone-d6): δ 9.00 (dd, 1H), 8.90 (dd, 1H), 8.41 (d, 1H), 7.84 (dd, 1H), 7.65 (d, 1H), 7.52 (dd, 1H), 6.91 (dd, 1H), 6.77 (br s, 2H), 5.97 (dd, 1H), 5.34 (dd, 1H). LRMS [M+H]=222.1.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1.CC1(C)O[C:21](=[O:22])[CH2:20][C:18](=[O:19])[O:17]1>O>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[C:8]2[C:7](=[CH:6][CH:5]=1)[O:12][C:21](=[O:22])[C:20]([C:18]([OH:19])=[O:17])=[CH:9]2
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2cc(OC(F)(F)F)ccc2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
5-trifluoromethoxy-salicylaldehyde (286.0 mg, 1.39 mmol) and Meldrum's acid (200 mg, 1.39 mmol) were combined in H2O (2 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 189.1 mg of 6-trifluoromethoxy-3-carboxy-coumarin in a 50% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]#N)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)C[OH:15].[OH-:17].[K+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]([OH:15])=[O:17])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2cccc(Br)c2)CC1
Reactant: OCCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)C1(c2cccc(Br)c2)CC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
1-(3-Bromophenyl)cyclopropanecarbonitrile (Reference compound 25-1, 5.0 g, 23 mmol) and ethylene glycol (20 mL) were added to a solution of potassium hydroxide (3.7 g, 66 mmol) in water (20 mL). The mixture was stirred at 140° C. for 4 hours. The reaction mixture was poured into a solution mixture of ice-water mL) and 6 N hydrochloric acid (50 mL). The precipitated solid was separated by filtration and dried under reduced pressure to give the title reference compound (4.7 q) as a brown solid (yield 87%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:14])[F:16])=[CH:9][C:8]=2[C:17]2[C:18]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:40](=[O:39])[CH2:41][OH:42])[CH2:34][CH2:35]4)=[O:28])[C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:3][CH2:4]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)CO)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f31) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[C:5]2[CH:18]=[CH:19][CH:20]=[CH:21][C:4]=2[NH:3]1.[H-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][N:3]1[C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=2[N:6]([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[C:2]1=[O:1])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)c1ccc(-n2c(=O)[nH]c3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)cc1
Reaction time: 0.08 h

Procedure:
To a stirred solution of ethyl 4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)benzoate from Step C (590 mg, 2.09 mmol) in DMF (10 mL) at 0° C. was added sodium hydride (104 mg of a 60% dispersion in mineral oil, 2.60 mmol). The mixture was stirred for 5 min, then tert-butyl bromoacetate (489 mg, 2.51 mmol) was added and stirring was continued for 3 h. The reaction mixture was partitioned between EtOAc (200 mL) and H2O (100 mL). The organic layer was washed with H2O (50 mL), then brine (50 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 0:100, to give the title compound. MS: m/z=397 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:36])=O)[CH2:30][CH2:29]3)=[N:10][C:11]([C:24]([F:27])([F:26])[F:25])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[OH:49][N:50]1C2C=CC=CC=2N=N1.[CH:59](N(C(C)C)CC)(C)C>ClCCl>[CH3:59][O:49][NH:50][C:34]([CH:31]1[CH2:32][CH2:33][N:28]([C:9]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[N:12]=[C:11]([C:24]([F:25])([F:27])[F:26])[N:10]=2)[CH2:29][CH2:30]1)=[O:36]
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)nc(N3CCC(C(=O)O)CC3)c2-c2ccc(F)cc2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CONC(=O)C1CCN(c2nc(C(F)(F)F)nc(-c3ccc(S(C)(=O)=O)cc3)c2-c2ccc(F)cc2)CC1
Reaction time: 2 h

Procedure:
A solution of 1-{5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(trifluoromethyl)pyrimidin-4-yl}piperidine-4-carboxylic acid (0.15 g, 0.30 mmol) in dichloromethane (5 ml) was treated with o-methyl hydroxylamine hydrochloride (0.028 g, 0.30 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.127 g, 0.663 mmol), 1-hydroxybenzotriazole (0.008 g, 0.066 mmol) and diisopropylethylamine (0.042 g, 0.33 mmol). After 2 hours of stirring the reaction mixture was poured onto ice-cold water, extracted with dichloromethane and washed with brine. Evaporation of the organic layer furnished the required compound. 1H-NMR (DMSO-d6) δ: 1.46 (m, 4H), 2.14 (m, 1H), 2.73-2.78 (m, 2H), 3.18 (s, 3H), 3.53 (s, 3H), 3.81-3.84 (m, 2H), 7.24 (d, 2H), 7.31-7.36 (m, 5H), 7.75 (d, 2H), 11.01 (br.s, 1H, D2O exchangeable); MS m/z: 535.1 (M++1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH:36]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH:36]1([NH-:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NC1CCCCC1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: [NH-]C1CCCCC1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 234 μl (2 mmol, 203 mg) of cyclohexylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.52) disappeared and the product (Rf=0.68) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/ethyl acetate 3:7). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and methanol of increasing methanol content. The fractions containing the product eluting with a 96:4 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (205 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.