Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O>[O:9]1[CH:13]=[CH:12][C:11]([C:2]2[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:10]1
Reactant: OB(O)c1ccoc1
Reactant: Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Oc1cccnc1-c1ccoc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
2-Bromopyridin-3-ol (200 mg, 1.15 mmol), 3-furan boronic acid (574 mg, 1.38 mmol), sodium carbonate (365 mg, 12.8 mmol) and Pd2(dppf)2Cl2 (187 mg, 0.23 mmol) were dissolved in dimethoxyethane/water 2 mL/1 mL, followed by stirring in microwave at 120° C. for 20 minutes. After the completion of the reaction, the reaction mixture was filtered using Celite. The filtrate was added with water, and extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate, and purified by column chromatography (ethyl acetate:hexane=1:3) to obtain 2-(furan-3-yl)pyridin-3-ol (50 mg, 27%).
Reaction SMILES: I[C:2]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[NH:7][C:8](=[O:10])[CH3:9].[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>CN(C=O)C.C(N(CC)CC)C.C(OCC)(=O)C.O.[Cu](I)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>[CH3:11][N:5]1[C:6]([NH:7][C:8](=[O:10])[CH3:9])=[C:2]([C:19]#[C:18][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4]1
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)Nc1c(I)c(-c2ccccc2)nn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1c(C#C[Si](C)(C)C)c(-c2ccccc2)nn1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
Nitrogen was bubbled through a mixture of N-(4-iodo-1-methyl-3-phenyl-1H-pyrazol-5-yl)acetamide (5 g, 15 mmol) in DMF (15 mL) and triethylamine (35 mL) for 15 min. Copper iodide (0.56 g, 3.0 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.53 g, 0.75 mmol) and ethynyltrimethylsilane (3.0 g, 30 mmol) were added and the reaction mixture was stirred in a sealed tube at 90° C. under nitrogen for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separation cartridge) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, isohexane/ethyl acetate 5:1 to 10:3) yielding the title compound as a solid (2.3 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH2:11][CH3:12])[C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[AlH3].C1(C)C=CC=CC=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH2:11][CH3:12])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(C)(C#N)c1cccc(Br)c1
Agent: [AlH3]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC(C)(CN)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
A solution of 2-(3-bromophenyl)-2-methylbutanenitrile (1678.5 mg, 7.049 mmol) in dry THF (28 mL) was cooled in an ice-bath. AlH3:(Me)2EtN complex, 0.5M in PhMe (28.20 mL of 0.5 M, 14.10 mmol) was added slowly dropwise and the resultant solution stirred at 0° C. for 30 mins. The mixture was allowed to warm to RT and stirred for 4.5 hours. The reaction was carefully quenched by dropwise addition of 1:1 THF:water (˜30 mL). The resulting suspension was stirred vigorously and filtered through a pad of celite. The collected solid was partitioned between EtOAc and brine and the aqueous layer further extracted with EtOAc (3×50 mL) and the combined organics dried over Na2SO4, filtered and concentrated under reduced pressure to give a light brown oil. The residue was purified on silica gel by flash column chromatography (5% MeOH in DCM, loaded in DCM, ˜200 mL silica) to give the product as a yellow oil (1137.8 mg, 67% Yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7](O)[CH3:8])([CH3:4])([CH3:3])[CH3:2].S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.Cl.[CH2:35]([O:42][C:43](=[O:61])[C@@H:44]([NH2:60])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[Cl:59])=[CH:48][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.[F:69][C:70]([F:85])([F:84])[S:71]([O:74][C@H:75]([CH3:83])[C:76]([O:78][C:79]([CH3:82])([CH3:81])[CH3:80])=[O:77])(=[O:73])=[O:72]>C(Cl)Cl>[F:84][C:70]([F:69])([F:85])[S:71]([O:74][C@H:75]([CH3:83])[C:76]([O:78][C:79]([CH3:80])([CH3:81])[CH3:82])=[O:77])(=[O:72])=[O:73].[CH2:35]([O:42][C:43](=[O:61])[C@@H:44]([NH:60][C@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])[CH3:8])[CH2:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[CH:54][C:53]=2[Cl:59])=[CH:48][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)OCc1ccccc1
Agent: C[C@@H](OS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C[C@H](N[C@@H](Cc1ccc(-c2cc(Cl)ccc2Cl)cc1)C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
Step 3′: t-Butyl (R)-2-(trifluoromethylsulfonyloxy)propionate was prepared from (R)-2-hydroxy-propionic acid tert-butyl ester (602 mg, 4.12 mmol), triflic anhydride (0.696 mL, 4.12 mmol) and 2,6-lutidine (0.480 mL, 4.12 mmol) in DCM (5 mL). To a suspension of ((S)-2-amino-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester hydrochloride (600 mg, 1.38 mmol) in dichloromethane (10 mL) was added triethylamine (0.574 mL, 4.12 mmol) at 0° C. After stirred for 10 min, a half amount of the freshly prepared t-butyl (R)-2-(trifluoromethylsulfonyloxy)propionate was added at room temperature and stirred for 1 hour. Additional triethylamine (0.574 mL, 4.12 mmol) and the rest of t-butyl (R)-2-(trifluoromethylsulfonyloxy)propionate were added at room temperature and stirred for additional 2 hours. The reaction mixture was washed with H2O and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/heptane) to give (S)-2-((S)-1-tert-butoxycarbonyl-ethylamino)-3-(2′,5′-dichloro-biphenyl-4-yl)-propionic acid benzyl ester (580 mg). 1H NMR (400 MHz, CDCl3) δ 1.24 (t, 3H, J=6.8 Hz), 1.41 (s, 9H), 3.00-3.07 (m, 2H), 3.26 (dd, 1H, J=7.1, 13.9 Hz), 3.70 (dd, 1H, J=7.1, 7.1 Hz), 5.09 (s, 2H), 7.20-7.42 (m, 12H); MS: m/z (MH+) 528.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH2:15]C(N)=O>>[Cl:14][C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[NH:15][C:1](=[O:2])[CH2:4]2
Reactant: NC(N)=O
Reactant: O=C(O)Cc1cc(Cl)ccc1C(=O)O
Product: O=C1Cc2cc(Cl)ccc2C(=O)N1
Reaction time: 0.25 h
Yield: 34 %

Procedure:
An amount of 2-(carboxymethyl)-4-chlorobenzoic acid (8.4 g, 39.14 mmol) and 2.82 g (47 mmol) of urea is vigorously stirred at 160° C. Solids were melted, boiled and hardened after 15 min. Continue to heat and blow nitrogen through to remove water generated from reaction until total dryness. After cooling, the solid is ground to fine powder. After successively washing with saturated NaHCO3 solution, water, methanol, ether and hexane, the powder is dried in oven (60° C.) overnight to give 2.6 g (34.0% yield) of light yellow solid: MS (ESI) m/z 194.0 (M−H)−1 Analysis for C9H6ClNO2, Calcd: C, 55.26; H, 3.09; N, 7.16. Found: C, 54.86; H, 2.96; N, 7.12
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]([NH2:47])[CH3:46]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:47][CH:45]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH3:46])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(N)c1ccccn1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)c4ccccn4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Yield: 93 %

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and (RS)-1-pyridin-2-yl-ethylamine: yield 93%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:11]=1)=[N:6][CH:7]=[CH:8][C:9]=2[CH3:10].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]2[C:5]([N:11]=1)=[N+:6]([O-:20])[CH:7]=[CH:8][C:9]=2[CH3:10]
Reactant: Cc1nc2nccc(C)c2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c([nH]1)c(C)cc[n+]2[O-]
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine (4.29 g) in chloroform (43 ml) was added m-chloroperbenzoic acid (80%, 7.55 g) at room temperature, and the mixture was refluxed under heating for 1 hr. After cooling to room temperature, the reaction mixture was directly purified by silica gel column chromatography (chloroform/methanol=9/1) and pulverized in ethyl acetate to give the objective compound (4.61 g) as a brown powder.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]([F:15])([F:14])[F:13])=O.[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20].C(O)(=O)C.N1CCCCC1>ClCCl>[C:19]([C:18]([C:17](=[O:22])[CH3:16])=[CH:1][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][C:12]([F:15])([F:14])[F:13])(=[O:21])[CH3:20]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccc(C=O)c(OC(F)(F)F)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C(=Cc1ccc(C#N)cc1OC(F)(F)F)C(C)=O
Yield: 99.4 %

Procedure:
3.32 g (15.43 mmol) of 4-formyl-3-(trifluoromethoxy)benzonitrile, 1.55 g (15.43 mmol) of 2,4-pentanedione, 1.39 g of acetic acid (23.15 mmol) and 262 mg (3.09 mmol) of piperidine are dissolved in 150 ml of dichloromethane and heated under reflux with an inverse water trap overnight. After complete conversion has been detected by a TLC check, the mixture is diluted with 100 ml of dichloromethane and washed with water and saturated sodium chloride solution. The solvent is removed in a rotary evaporator. 4.56 g (99% of theory) of crude 4-(2-acetyl-3-oxobut-1-en-1-yl)-3-(trifluoromethoxy)benzonitrile are obtained and are reacted directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B(O)O)[CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=1)=[O:13].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:1][C:2]1[CH:7]=[C:6]([C:16]2[CH:15]=[C:14]([C:12](=[O:13])[CH3:11])[CH:19]=[CH:18][CH:17]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc(-c2ccnc(Cl)c2)c1
Reaction time: 6 h
Yield: 58.7 %

Procedure:
2-Chloropyridine-4-boronic acid (11.0 g, 69.9 mmol), 3-Bromoacetophenone (11.2 mL, 83.9 mmol, 1.2 eq.), Na2CO3 (35 mL, 244.65 mmol, 3.5 eq.) and dppfPdCl2 (572 mg, 0.07 mmol, 0.01 eq.) were mixed in THF (200 mL). The mixture was heated to reflux and continued at this temperature for 6 hours. It was then cooled and concentrated in vacuo. The residue was partitioned between DCM and water (100 mL/40 mL). The layers were separated and the aqueous layer was washed further with DCM (2×40 mL). The combined organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated, and the residue was chromatographed using 1/1 hexane/EtOAc to give 1-[3-(2-Chloro-pyridin-4-yl)-phenyl]-ethanone as a white solid (9.5 g, 58%). MS: m/z 232.1 [MH+].
Reaction SMILES: C(OC(N(CC([O-])=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](CO)[N:10]=1)=O)(C)(C)C.FC1C=CC([S:28]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[S:40][CH:41]=[CH:42][N:43]=3)=[CH:35][CH:34]=2)(=[O:30])=[O:29])=CC=1>>[S:40]1[CH:41]=[CH:42][N:43]=[C:39]1[C:36]1[CH:35]=[CH:34][C:33]([CH2:32][NH:31][S:28]([C:12]2[CH:11]=[N:10][CH:9]=[CH:14][CH:13]=2)(=[O:30])=[O:29])=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N(CC(=O)[O-])c1cccc(CO)n1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1ccc(F)cc1
Product: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl([tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate (101 mg, 0.298 mmol) obtained in Reference Example 3-(b), and using 4-fluoro-N-[4-(thiazol-2-yl)benzyl]benzenesulfonamide (105 mg, 0.301 mmol) obtained in Reference Example 6 in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide to afford the title compound (181 mg) as a white foam. (Yield: 91%) Mass spectrum (FAB, m/z): 669 (M++1).
Reaction SMILES: C([O:8][C:9]1[C:42]([CH3:43])=[CH:41][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[CH2:33][CH2:32][C:31]5[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=5[NH:29][C:28]4=[O:40])[CH2:23][CH2:22]3)[CH:16]=2)=[O:14])=[CH:11][C:10]=1[CH3:44])C1C=CC=CC=1.[H][H]>[Pd].CO>[OH:8][C:9]1[C:42]([CH3:43])=[CH:41][C:12]([C:13]([C:15]2[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:22][CH2:23][CH:24]([N:27]4[CH2:33][CH2:32][C:31]5[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=5[NH:29][C:28]4=[O:40])[CH2:25][CH2:26]3)[CH:16]=2)=[O:14])=[CH:11][C:10]=1[CH3:44]
Reactant: [H][H]
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c(OCc5ccccc5)c(C)c4)ncn3)CC1)C(=O)N2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c(O)c(C)c4)ncn3)CC1)C(=O)N2

Procedure:
70 mg (0.10 mmol) 3-{1-[6-(4-benzyloxy-3,5-dimethyl-benzoyl)-pyrimidin-4-yl]-piperidin-4-yl}-7-methoxy-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 20 mg palladium on charcoal (Pd/C 10%) in 10 mL MeOH were hydrogenated for 30 min at RT in a hydrogen atmosphere of 10 psi. After filtration of the reaction mixture the solvent was eliminated i. vac. and the residue was purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13]([O-:16])(=O)=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:19]>C1(C)C(C)=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][S:13]([Cl:19])(=[O:16])=[O:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(NCCS(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(NCCS(=O)(=O)Cl)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 45.3 %

Procedure:
A mixture of sodium 2-[(4-nitrophenyl)amino]ethanesulfonate (8) (5.36 g, 0.02 mol), phosphorus pentachloride (4.58 g, 0.022 mol) and 50 mL of anhydrous xylene was heated at about 40-50° C. for 4 hours. After remaining at room temperature overnight, the mixture was heated for 3 hours in a boiling water bath. The resulting mixture was filtered while hot and the insoluble matter was washed three times with hot xylene. The filtrate was left to cool. A yellow solid formed, and was filtered off and reslurried in water. 2.4 g of expected product were isolated.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28](O)=[O:29])=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:35]1([CH2:38][N:39]2[CH2:44][CH2:43][N:42]([C@H:45]3[CH2:50][CH2:49][C@H:48]([NH2:51])[CH2:47][CH2:46]3)[CH2:41][CH2:40]2)[CH2:37][CH2:36]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([NH:51][C@H:48]5[CH2:47][CH2:46][C@H:45]([N:42]6[CH2:41][CH2:40][N:39]([CH2:38][CH:35]7[CH2:36][CH2:37]7)[CH2:44][CH2:43]6)[CH2:50][CH2:49]5)=[O:29])=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8](=[O:32])[C@H:7]2[CH2:33][CH3:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H]1CC[C@H](N2CCN(CC3CC3)CC2)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@H](N5CCN(CC6CC6)CC5)CC4)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Reaction time: 2 h

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylic acid 4f (150 mg, 0.32 mmol), (trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 16b (76 mg, 0.32 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (103 mg, 0.32 mmol) were dissolved in 20 mL of dichloromethane followed by the addition of diisopropylethylamine (103 mg, 0.80 mmol). The reaction solution was stirred for 2 hours. The resulting solution was added with 20 mL of saturated ammonium chloride solution, seperated, the organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparation plate to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(trans)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-2,2-dimethyl-3H-benzofuran-4-carboxamide 16 (130 mg, yield: 59.0%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)[N:10]=1.[C:23](Cl)(=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C([O-])(O)=O.[Na+].Cl.C([O-])([O-])=O.[K+].[K+]>ClCCCl.O.CO.C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([C:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:2][O:1][C:23](=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[NH:13][N:12]=2)[CH:19]=[CH:18][CH:17]=1)[CH3:22]
Reactant: CCOc1cccc(-c2n[nH]c(-c3ccccc3CO)n2)c1
Reactant: CCCCCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCCCCCCC(=O)OCc1ccccc1-c1nc(-c2cccc(OCC)c2)n[nH]1
Temperature: 25 °C
Yield: 61 %

Procedure:
A mixture of 5-(2-hydroxymethylphenyl)-3-(3-ethoxyphenyl)-1H-1,2,4-triazole (2.36 g, 8 mmole) and octanoyl chloride (1.6 ml, 9.4 mmole) in 1,2-dichloroethane (24 ml) is heated to the reflux temperature with stirring. When the reaction, which is followed by thin layer chromatography (silica-gel plates, toluene: ethyl acetate 1:1), is complete, the reaction mixture is cooled to room temperature and methanol (8 ml) is added. Then an excess of NaHCO3 (1.21 g, 14.4 mmole) is added to neutralize the hydrochloric acid formed during the reaction, followed, after a few minutes, by anhydrous K2CO3 (0.062 g, 0.45 mmole). When the partial transesterification of the N,O-diacyl derivative into the desired monoacyloxy one is complete, the reaction mixture is diluted with water (20 ml), the organic phase is separated and the aqueous one is extracted with methylene chloride (2×10 ml). The organic extracts are combined, washed with water, dried over Na2SO4 and concentrated to dryness giving a row residue which is purified by crystallization from hexane. Yield: 61%. M.p. 87°-89° C.
Reaction SMILES: OC(C)(C)CN1C=C[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][O:56][CH2:57][C:58]1N=C(N)[S:60][N:59]=1>ClCCl>[CH3:55][O:56][CH2:57][C:58]1[N:5]=[C:6]([NH:9][C:10](=[O:30])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])=[CH:18][C:17]2=[O:29])[CH2:12][CH:13]([CH3:15])[CH3:14])[S:60][N:59]=1
Reactant: COCc1nsc(N)n1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COCc1nsc(NC(=O)[C@H](CC(C)C)N2CC(Oc3ccccc3Cl)=CC2=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 64, 94 mg, 0.29 mmol) in dichloromethane (1.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg, 0.32 mmol) and 1-hydroxybenzotriazole (42 mg, 0.31 mmol). The resulting solution was stirred for 5 min before 3-methoxymethyl-[1,2,4]thiadiazol-5-ylamine (50 mg, 0.34 mmol) was added and the resulting mixture stirred at 25° C. overnight. The mixture was washed with saturated ammonium chloride (1 mL), evaporated and the crude product purified by HPLC (Gilson semi-prep; Supelcosil ABZ+Plus 12 μM 25 cm×21.2 mm column 20-95% acetonitrile/water) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (3-methoxymethyl-[1,2,4]thiadiazol-5-yl)-amide (62 mg, 47%) as a light yellow solid: HR-ES-MS m/z calculated for C20H23ClN4O4S [M+H]+ 451.1202, observed 451.1202; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92 (d, J=6.6 Hz, 3H), 0.95 (d, J=6.6 Hz, 3H), 1.48 (br. s., 1H), 1.60-1.76 (m, 1H), 1.79-1.95 (m, 1H), 3.33 (s, 3H), 4.30 (d, J=18.1 Hz, 1H), 4.51 (d, J=18.1 Hz, 1H), 4.52 (s, 2H), 4.84 (s, 1H), 5.02 (dd, J=10.9, 4.5 Hz, 1H), 7.37 (td, J=7.5, 0.9 Hz, 1H), 7.47 (t, J=7.5 Hz, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 13.40 (s, 1H).
Reaction SMILES: [N+]([O-])([O-])=O.[Na+].[F:6][C:7]([F:18])([F:17])[C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[N:13][NH:14]2)=[CH:10][CH:9]=1.S(=O)(=O)(O)O.O.[NH3:25]>>[NH2:25][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:8]=1[C:7]([F:6])([F:17])[F:18])[NH:14][N:13]=[CH:12]2
Reactant: N
Reactant: FC(F)(F)c1ccc2cn[nH]c2c1
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1cc2cn[nH]c2cc1C(F)(F)F
Reaction time: 1 h
Yield: 94 %

Procedure:
Under ice-cooling, 1.01 g (12.0 mmol) of sodium nitrate was added to a mixture of 1.54 g (8.29 mmol) of 6-trifluoromethylindazole and 5 ml of concentrated sulfuric acid, and the mixture was stirred for 1 hour. The reaction mixture was poured onto ice and after ammonia water was added dropwise to the mixture under ice-cooling until pH reached 10 or higher, the precipitated solid was collected by filtration and then washed with water, followed by drying. The resulting crude product was dissolved in 50 ml of methanol, activated carbon was added to the mixture, and the mixture was filtered. 0.20 g of 5% Palladium-on-carbon was added to the filtrate, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hours. The mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give 1.57 g (yield: 94%, two steps) of 5-amino-6-trifluoromethylindazole.