Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH:9]=2)[CH2:4][CH2:3]1.[C:21]([C:23]1[O:27][C:26]([C:28](Cl)=[O:29])=[CH:25][CH:24]=1)#[N:22].CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:28]([C:26]3[O:27][C:23]([C:21]#[N:22])=[CH:24][CH:25]=3)=[O:29])=[C:10]([C:15]3[S:16][CH:17]=[CH:18][C:19]=3[CH3:20])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1N
Reactant: N#Cc1ccc(C(=O)Cl)o1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccsc1-c1cc(N2CCN(C)CC2)ccc1NC(=O)c1ccc(C#N)o1
Yield: 35.8 %

Procedure:
1-Methyl-4-[3-(3-methyl-thiophen-2-yl)-4-nitro-phenyl]-piperazine (60 mg, 0.18 mmol, as prepared in the previous step) was stirred with 40 mg 5% Pd—C in MeOH (5 mL) under H2 (1 atm) for 2 h. The reaction was filtered through Celite and concentrated in vacuo to afford 40 mg (72%) of 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine as a brown solid, which was used immediately without further purification. Using a procedure similar to Example 9, step (c), 4-(4-methyl-piperazin-1-yl)-2-(3-methyl-thiophen-2-yl)-phenylamine (40 mg, 0.13 mmol) was allowed to react with 5-cyano-furan-2-carbonyl chloride (30 mg, 0.19 mmol, as prepared in Example 9, step (c)) in the presence of DIEA (61 μL, 0.34 mmol) to afford 18.9 mg (36%) of the title compound as a yellow solid. 1H-NMR (CDCl3; 400 MHz): δ 2.13 (s, 3H), 2.38 (s, 3H), 2.59-2.62 (m, 4H), 3.24-3.27 (m, 4H), 6.92 (d, 1H, J=2.8 Hz), 7.06 (d, 1H, J=5.1Hz), 7.15 (d, 1H, J=3.7 Hz), 7.19 (d, 1H, J=3.7 Hz), 7.02 (dd, 1H, J=2.8, 9.0 Hz), 7.42 (d, 1H, J=5.1 Hz), 8.11 (s, 1H), 8.34 (d, 1H, J=9.0 Hz); Mass spectrum (ESI, m/z): Calcd. for C22H22N4O2S, 407.1 (M+H), found 407.1.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:39])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[N:25]([CH:26]=3)[C:24]3[CH:27]=[CH:28][C:29]([O:31][C:32]([C@@H:34]5CCC[NH:35]5)=[O:33])=[CH:30][C:23]=3[S:22]4)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ON1C(=O)[CH2:44][CH2:43][C:42]1=O.C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O>>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:39])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[N:25]([CH:26]=3)[C:24]3[CH:27]=[CH:28][C:29]([O:31][C:32](=[O:33])[C@H:34]([NH2:35])[CH:43]([CH3:44])[CH3:42])=[CH:30][C:23]=3[S:22]4)=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1O
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OC(=O)[C@@H]5CCCN5)ccc34)cc2)no1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)[C@@H](N)C(=O)Oc1ccc2c(c1)sc1nc(-c3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)cn12

Procedure:
In a manner similar to Step A, (2S)-pyrrolidine-2-carboxylic acid 2-{4-[3-(5-tert-butyl-isoxazol-3-yl)-ureido]-phenyl}-benzo[d]imidazo[2,1-b]thiazol-7-yl ester was made using Boc-L-proline N-hydroxysuccinimide; LC-MS: ESI 545 (M+H)+. [Compound B6]
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Li][CH2:17][CH2:18]CC.C(I)C>C1COCC1>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=3)[CH:5]([CH2:17][CH3:18])[C:4]=2[CH:3]=1
Reactant: [Li]CCCC
Reactant: Clc1ccc2c(c1)Cc1cc(Cl)ccc1-2
Solvent: C1CCOC1
Solvent: CCI
Product: CCC1c2cc(Cl)ccc2-c2ccc(Cl)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 119.3 %

Procedure:
To a solution of 2,7-dichlorofluorene (1.0 g, 4.3 mmol) in 3 mL of THF was added n-BuLi (2 mL, 5.0 mmol) at -78° C. under argon and the solution was stirred at -78° C. for 0.5 hours. A solution of C2H5I (0.78 g, 5.0 mmol) in 1 mL of THF was poured into the solution and stirred at -78° for 15 min, quenched with NH4Cl solution, concentrated and extracted the residue with ethyl acetate, dried with MgSO4 and evaporated to get the crude product which was purified by silica gel column chromatography using hexane as the eluent to obtain 1.35 g (74%) of 2,7-dichloro-9-ethylfluorene was a white solid, mp 80°-83° C.: IR: 3435, 1453, 1422, 1296, 1160, 1072, 885, 807 cm-1.H1NMR (CDCl3, 300 MHz) δ 7.2-7.8 (m, 6H), 3.9-4.1 (t, 1H), 2.0-2.2 (m, 2H), 0.6-0.8 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH3:15])([CH3:14])[CH2:7][CH2:6]2.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:6]1[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9](=[O:13])[C:8]([CH3:15])([CH3:14])[CH2:7]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)CCC(C)(C)C2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)C(Br)CC(C)(C)C2=O
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To a mixture of 6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (3.30 g, 16.2 mmol) and 1-bromopyrrolidine-2,5-dione (2.88 g, 16.2 mmol) in 50 mL of CCl4, was added AIBN (0.265 g, 1.62 mmol). The mixture was heated to reflux for three hours. The reaction was cooled to RT and the reaction was quenched with water (25 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and the residue was purified by column chromatography (0-50% EtOAc/Hexane to provide the title compound as a white solid (3.92 g, 86% yield). MS m/z: 284.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[OH-].[K+].CN(C)C=O.[F:18][C:19]([F:23])=[C:20]([F:22])[F:21]>CCOCC.O>[F:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([O:8][C:20]([F:22])([F:21])[CH:19]([F:23])[F:18])[CH:7]=1
Reactant: COc1ncc(O)cc1F
Reactant: FC(F)=C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1ncc(OC(F)(F)C(F)F)cc1F
Temperature: 70 °C
Reaction time: 3 h

Procedure:
3-Fluoro-2-methoxy-5-pyridinol (1.60 g, 11.2 mmol) and 0.04 g (0.7 mmol) of potassium hydroxide were added to 10 ml of dimethylformamide and the mixture blanketed with nitrogen and heated to 70° C. with stirring. An excess of tetrafluoroethylene was introduced into the liquid by means of a sparge tube. After stirring 4 hours at 70° C. no reaction was observed so another 0.04 g of potassium hydroxide was added and the tetrafluoroethylene addition continued. The reaction was indicated to be complete by F19 nmr after 3 hours. The mixture was allowed to cool and was then poured into a mixture of 50 ml of water and 60 ml of ether. The ethereal layer was extracted with 2-25 ml portions of water and one of saturated aqueous sodium chloride and dried over sodium sulfate. The combined aqueous extracts were extracted with ether and the ethereal layer dried. The combined ethereal solutions were concentrated by evaporation under reduced pressure to obtain 1.65 g of the title compound as a yellow oil. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)=O.[F:22][C:23]([F:31])([F:30])[C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:24](=[O:29])[C:23]([F:31])([F:30])[F:22])[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1cccc(Cl)c1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCCCCCC
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc(OC(F)(F)F)cc2c(-c2cccc(Cl)c2)c1C(=O)C(F)(F)F
Reaction time: 60 h
Yield: 58 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3-chloro-phenyl)-methanone [example A7] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 60 h and heptane/ethyl acetate (1:2) was used. Yield: 58%; MS: m/z=433 (M).
Reaction SMILES: [N:1]1([CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-])=O)[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.S1C=CC=C1.N.[H][H]>CO.[Pt]>[N:1]1([CH:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:8]=[C:9]([NH2:14])[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: N
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1N
Yield: 99 %

Procedure:
(a-3) A mixture of 3.4 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzenamine, 1 part of a solution of thiophene in methanol 4%, 80 parts of methanol and 80 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 2.64 parts (99%) of 4-[(1H-imidazol-1-yl)-phenylmethyl]-1,2-benzenediamine as a residue (int. 126), or alternatively
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=O)[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C([C:30]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:31])(C)(C)C.C[OH:53]>ClCCl.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13]([CH:24]=[CH:32][C:30]([OH:53])=[O:31])[CH:14]=[C:15]([N+:21]([O-:23])=[O:22])[CH:16]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CO
Reactant: CC(C)(C)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)C=Cc1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(Cl)c(Cl)c3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 2-((3,4-dichlorophenyl)amino)-4-hydroxy-6-nitroquinazoline-8-carbaldehyde (250 mg) and t-butylcarbonylmethylenetriphenylphosphorane (274 mg) in dichloromethane (15 mL) was stirred at room temperature for 3 h. The resulting solution was concentrated and the residue was dissolved in tetrahydrofuran (10 mL). Hydrochloric acid (1 N, 4 mL) was added, and the reaction was stirred at room temperature for 0.5 h. The solution was then evaporated to afford a brown solid, which was suspended in methanol (30 mL) and tetrahydrofuran (3 mL). The product was isolated by filtration, washed with methanol and dried to afford the title compound as a brown solid (71 mg). 1H NMR (300 MHz, DMSO-d6): 8.74 (bd, J=2.1 Hz, 1H), 8.64 (bd, J=1.8 Hz, 1H), 8.23 (m, 2H), 7.54 (m, 2H), 6.80 (d, J=16.2 Hz, 1H). HPLC Method A: 6.13 min. MS (APCI−): m/z 419, 421.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[C:19](Cl)=[N:18][S:17][N:16]=1.Cl>CN(C=O)C.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:19]2[C:15]([Cl:14])=[N:16][S:17][N:18]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nsnc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nsnc2Cl)CC1
Temperature: 100 °C
Yield: 82.4 %

Procedure:
1-Boc-piperazine (30.2 g, 165 mmol) was dissolved in DMF (30.0 mL) and heated to 100° C. 3,4-Dichloro-1,2,5-thiadiazole (7.5 mL, 80 mmol) was added dropwise with stirring and the mixture heated at 100° C. for 5.5 h. The reaction mixture was diluted with H2O and the pH adjusted to 2.0 with 1N HCl. The resulting solids were filtered, washed with H2O and dried under vacuum to give 20.1 g (83%) of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid tert-butyl ester as a tan solid. 1H NMR (DMSO-d6) 3.48 (m, 4H), 3.36 (m, 4H), 1.42 (s, 9H) ppm. LC-MS (MH+)=205 (-Boc).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:5]([OH:7])=[O:6].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>[OH-].[Na+]>[CH3:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: C1CCNC1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)cc(N2CCCC2)n1

Procedure:
A solution of 2-chloro-6-methyl-isonicotinic acid (1.03 g, 5.98 mmol) in pyrrolidine (5 mL) is stirred at 85° C. for 6 days. The mixture is diluted with 1 N aq. NaOH (40 mL) and the solvent is removed in vacuo. The crude product is again dissolved in 1 N aq. NaOH (3 mL) and methanol (1 mL) and purified by MPLC on RP-C18-silica gel to give 2-methyl-6-pyrrolidin-1-yl-isonicotinic acid (1.18 g) as a beige solid; LC-MS: tR=0.52 min, [M+H]+=207.06; 1H NMR (D6-DMSO): δ 1.89-1.94 (m, 4H), 2.27 (s, 3H), 3.33-3.38 (m, 4H), 6.61 (s, 1H), 6.77 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:15])[CH2:12][C:13]#[CH:14]>C(N(CC)CC)C.CN(C)C=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:15][CH2:11][CH2:12][C:13]#[C:14][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cccc(C#CCCO)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.7 %

Procedure:
Into a 500-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-bromobenzoic acid (10 g, 49.75 mmol, 1.00 equiv) in triethylamine/N,N-dimethylformamide (100/20 mL), but-3-yn-1-ol (6.98 g, 99.57 mmol, 2.00 equiv), copper(I) iodide (1.90 g, 9.97 mmol, 0.20 equiv), Pd(PPh3)2Cl2 (6.98 g, 9.94 mmol, 0.20 equiv). The resulting solution was stirred overnight at 80° C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 11-12 with sodium hydroxide (1 mol/L). The resulting solution was extracted with 3×300 mL of dichloromethane and the aqueous layers combined. The solution was adjusted to pH 1-2 with hydrochloric acid (1 mol/L). The resulting solution was extracted with 5×300 mL of dichloromethane and the organic layers combined, dried over sodium sulfate, and concentrated under vacuum. This resulted in 10 g crude product as brown oil.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Br:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Br:30])[C:19]=1[F:31].CC(=O)OCC>CN(C=O)C>[Br:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Br:30])[C:19]=1[F:31]
Reactant: C=C(c1cc(Br)c(F)c(Br)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Br)c(F)c(Br)c4)(C(F)(F)F)C3)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.8 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (34 mg, 0.14 mmol) in DMF (3 mL) was added 1,3-dibromo-2-fluoro-5-(3,3,3-trifluoro-prop-1-en-2-yl)benzene (50 mg, 0.14 mmol) and TEA (15 mg, 0.14 mmol) at rt. The mixture was stirred at 25° C. for 12 h, quenched with water, extracted with EA (3×10 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography eluted with PE:EA (5:1) to give the final title compound 5-(5-(3,5-dibromo-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (50 mg; yield 59%) as solid. 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 7.92-7.68 (m, 5H), 4.45-4.40 (q, J=22 Hz, 1H), 4.34-4.30 (q, J=22 Hz, 1H), 1.48 (s, 6H) ppm; HPLC purity: 96.9% at 220 nm and 98.4% at 254 nm; MS: m/z=552.0 (M+1, ESI+).
Reaction SMILES: C(C1N=C(N2CC[C@H](O)C2)C2C(=NN(CC3C(C)=NON=3)N=2)N=1)(C)(C)C.[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([O:45]C(=O)C(F)(F)F)[CH2:41]2)[C:34]2[N:39]=[N:38][NH:37][C:35]=2[N:36]=1)([CH3:30])([CH3:29])[CH3:28].Br[CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=1[Cl:61]>>[C:27]([C:31]1[N:32]=[C:33]([N:40]2[CH2:44][CH2:43][C@H:42]([OH:45])[CH2:41]2)[C:34]2[C:35](=[N:37][N:38]([CH2:53][C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([Cl:60])[C:55]=3[Cl:61])[N:39]=2)[N:36]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1nc(N2CC[C@H](OC(=O)C(F)(F)F)C2)c2nn[nH]c2n1
Reactant: Clc1cccc(CBr)c1Cl
Agent: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CC[C@H](O)C3)c2n1
Product: CC(C)(C)c1nc(N2CC[C@H](O)C2)c2nn(Cc3cccc(Cl)c3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of (S)-1-[5-tert-Butyl-2-(4-methyl-furazan-3-ylmethyl)-2H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-pyrrolidin-3-ol (example 73), the title compound was prepared from Trifluoro-acetic acid (S)-1-(5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-yl-ester and 1-(bromomethyl)-2,3-dichlorobenzene and isolated as light brown gum. MS (m/e): 421.3 (MH+).
Reaction SMILES: C[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=C[C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([OH:18])(=[O:17])[CH3:16].O.S(=O)(=O)(O)O>[O-2].[O-2].[O-2].[Cr+6]>[N+:8]([C:6]1[CH:7]=[CH:2][C:3]([C:11]([F:12])([F:13])[F:14])=[C:16]([CH:5]=1)[C:15]([OH:18])=[O:17])([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1C(F)(F)F
Reactant: CC(=O)O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1C(F)(F)F

Procedure:
5-Nitro-2-trifluoromethyl-benzoic acid is prepared from the known 2-methyl-4-nitro-1-trifluoromethyl-benzene by oxidation with chromium trioxide in an acetic acid/water/sulfuric acid mixture following a procedure described by Aeberli et al. [P. Aeberli, P. Eden, J. H. Gogerty, W. J. Houlihan, C. Penberthy, J. Med. Chem. 18, 177 (1975)]: colourless solid, MS (ISN): 233.9 M−H−.
Reaction SMILES: N1CCCC[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[OH:40][C:41]([C:43](F)(F)F)=[O:42].[N:47]1([CH2:53][C:54]([OH:56])=[O:55])CCNCC1>CN(C=O)C.CN1C(=O)CCC1>[NH2:47][C@H:53]([C:54]([OH:56])=[O:55])[CH2:2][CH2:43][C:41](=[O:42])[OH:40]
Reactant: O=C(O)C(F)(F)F
Reactant: C1CCNCC1
Reactant: O=C(O)CN1CCNCC1
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
Solvent: CN1CCCC1=O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Approximately 10 mg of Fmoc-Glu-Fib-Trityl-chloride resin was treated with 20% (v/v) piperidine in DMF (2 mL×1 min, filtered, then 2 mL×5 min), filtered and washed (NMP). 4-(Fmoc-amino)benzoic acid (P/N: Bachem, B-3260; 10 eqv to Glu-Fib amount on the resin) was activated with HATU (P/N: Applied Biosystems 4317033, 9.5 eqv) and N,N-Diisopropylethylamine (30 eqv) in NMP (˜1 mL), added to the resin and mixed for 30 min. Resin was then filtered, washed with NMP, and Fmoc group was cleaved. Piperazine acetic acid-TFA salt (10 eqv) was then activated using HATU (9.5 eqv) and N,N-Diisopropylethylamine (60 eqv) in NMP (˜1.5 mL) and added to the resin. After 30 min resin was washed with NMP followed by CH3CN. Conjugated peptide was cleaved (and deprotected) from resin using 95:5 TFA-water (200 μL, 2 h) and precipitated using Et2O. Analysis of Compound (38) (see FIG. 30) was performed using MALDI-TOF (Sinapinic acid matrix, Calculated [M+H]+=1843.8, Observed [M+H]+=1844.9).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:29]([O:32][CH2:33]Cl)[CH2:30][CH3:31]>CN(C)C=O.O.CO>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:33][O:32][CH2:29][CH2:30][CH3:31])[C:19](=[O:24])[N:18]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CCCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CCCOCn1c(=O)c2c(ncn2Cc2ccccc2)n(CC(C)C)c1=O
Reaction time: 1 h

Procedure:
0.86 g (6.2 mmol) of potassium carbonate was added at 60° C. to a suspension of 1.16 g (3.9 mmol) of 7-benzyl-3-isobutylxanthine from stage c) in 60 ml of dimethylformamide and the mixture was stirred at this temperature for 1 hour. 0.56 ml (5.1 mmol) of propoxymethyl chloride was then added dropwise and the mixture was stirred at 80° C. for 5.5 hours. 12 ml of water and 5 ml of methanol were then added, the mixture was allowed to stand overnight, 60 ml of water were again added and the mixture was extracted four times using 150 ml of methyl tert-butyl ether each time. The combined organic phases were washed with 200 ml of water, dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane.
Reaction SMILES: Cl.ClCCN1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O-:14])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:14][C:6]1[CH:7]=[CH:8][C:9]([O:14][C:11]2[C:8]3[C:7](=[CH:6][C:11]([O:14][CH3:11])=[CH:10][CH:9]=3)[CH:8]=[CH:9][C:10]=2[C:8]2[CH:7]=[CH:6][CH:7]=[C:10]([O:14][CH3:11])[CH:9]=2)=[CH:10][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(O)cc2)c1
Temperature: 25 °C
Yield: 320 %

Procedure:
A solution of 1.5 g (4 mmol) of 1-(4-hydroxyphenoxy)-2-(3-methoxyphenyl)-6-methoxynaphthalene in 40 mL of DMF was prepared. To this solution was added 920 mg (5 mmol) of 2-chloroethylpiperidine hydrochloride and 5.2 g (16 mmol) of Cs2CO3, the reaction was stirred at ambient temperature under a nitrogen atmosphere for sixteen hours. The solvents were removed by evaporation and the residue partioned between water and EtOAc. The EtOAc layer was washed with water, then brine, dried with Na2SO4, and evaporated to dryness. The residue was dissolved in 10 mL of MeOH ane 1 mL of 5N HCl was added. The solvents were removed by evaporation and the product crystallized from EtOAc. This yielded 1.8 g of the title compound as a white solid, mp 161–162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:18][CH2:19][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH2:21][CH2:22]2)=[N:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cnc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 58 mL of chloroform, the obtained (7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde was dissolved, 2.67 g of tert-butyl (piperidin-4-yl)carbamate and 0.80 g of acetic acid were added, and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, 4.23 g of sodium triacetoxyborohydride was added, and the mixture was stirred for 15 hours. Thereto was added a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using silica gel; Silica Gel 60N made by KANTO CHEMICAL CO., INC. and an eluent of chloroform:methanol=10:1 to obtain 4.36 g of tert-butyl (1-(2-(7-methoxy-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white solid.