Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[OH:13])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:11])[CH3:12])=[CH:6][C:5]=1[OH:13]
Reactant: CC(C)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1ccc(N)c(O)c1
Yield: 80.1 %

Procedure:
To a solution of 2-nitro-5-isopropylphenol(1 g, 6.4 mmol) in methanol(50 mL) was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(775 mg, 93%). 1H NMR (CD3OD): δ 6.71-6.44 (m, 3H), 2.73 (m, 1H), 1.20 (d, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46]([OH:48])=O)[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:43])[CH3:42])[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:30])[CH3:29])[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].CC(=O)CC(=O)C.[F:74][C:75]1[CH:80]=[CH:79][C:78]([N:81]=[C:82]=[O:83])=[CH:77][CH:76]=1.FC(F)(F)C(O)=O>O.CO.O1CCOCC1.N1C=CC=CC=1>[NH2:1][CH2:2][C@H:3]1[O:7][CH:6]([O:8][C@@H:9]([C@@H:49]2[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]2[N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:41]([CH3:42])[CH3:43])[NH:18][C:19](=[O:39])[CH:20]([CH:32]3[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]3)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:27])=[O:26])[C:82](=[O:83])[N:81]([C:78]3[CH:79]=[CH:80][C:75]([F:74])=[CH:76][CH:77]=3)[C:46]2=[O:48])[C@H:5]([O:64][CH3:65])[C@H:4]1[OH:66]
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Reactant: O=C=Nc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CC(=O)CC(C)=O
Product: CO[C@H]1C(O[C@H](C2C(=O)N(c3ccc(F)cc3)C(=O)N2CCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)O[C@H](CN)[C@@H]1O
Reaction time: 8 h

Procedure:
To a solution of 47.3 mg (50 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11, 15-pentaazaheptadecane-1,17-dioic acid λmax nm in water=259) in 2.5 ml of methanol is added 200 μl of pyridine and 200 μl of 2,4-pentanedione at room temperature. The reaction mixture is stirred overnight (the reaction is monitored by mass spectroscopy (MS)). After the reaction is complete, the volatile materials are removed under reduced pressure. N,N-dimethylformamide (DMF) (3 ml) is added to the residue, followed by addition of 13.0 mg (95 μmol) of 4-fluorophenyl isocyanate. The reaction mixture is stirred at room temperature for 50 hours (the reaction was monitored by MS). The volatile materials are removed under reduced pressure to afford a residue to which is added 5 ml of 0.5% trifluoroacetic acid (TFA) in a 1:1 mixture of water and p-dioxane. The mixture is stirred at room temperature for 2 hours. The reaction is monitored by MS and the desired product is identified by liquid chromatography/mass spectrum (LC/MS). After concentration of volatiles to about one ml, 24 mg (44% yield) of the desired product is obtained as a colorless solid using preparative high pressure liquid chromatography (HPLC).
Reaction SMILES: [H-].[Na+].[ClH:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:22])[C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)=[CH:7][CH:6]=1.Br[CH2:24][C:25]([O:27][CH2:28]C)=[O:26].C(=O)(O)[O-].[Na+]>CN(C)C=O>[ClH:3].[C:25]([CH2:24][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][CH:15]([OH:22])[C:16]2[N:17]=[C:18]([CH3:21])[S:19][CH:20]=2)=[CH:7][CH:6]=1)([O:27][CH3:28])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: Cc1nc(C(O)CNCCc2ccc(O)cc2)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(CCNCC(O)c2csc(C)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
100 mg (2.1 mmol) of Sodium hydride dispersion (50% in paraffin oil) are added to 280 mg (1 mmol) of N-[2-(4-hydroxyphenyl)ethyl]-2-hydroxy-2-(2-methylthiazol-4-yl)ethanamine hydrochloride dissolved in 7 ml of absolute dimethyl formamide. After stirring at room temperature for 15 minutes, the solution of 153 mg (1 mmol) of ethyl bromoacetate in 3 ml of absolute dimethylformamide is rapidly added dropwise. The mixture is then stirred overnight, 20 ml of saturated sodium bicarbonate solution are added, and extraction with methylene chloride is carried out. The extracts are dried, concentrated and, after dissolution in ether/methanol, the hydrochloride is precipitated with ethereal hydrochloric acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])(O)=O.[Na+].Cl[CH2:18][C:19](Cl)=[O:20]>CC(C)CC(=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C1COc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
Mix 2-amino-5-nitro-phenol (10.0 g, 64.9 mmol) and NaHCO3 (13.1 g, 155.7 mmol) in 4-methyl-pentan-2-one (40 mL) and water (40 mL). Cool the mixture to 0° C. and slowly add chloroacetyl chloride (6.0 mL, 75.3 mmol) with stirring. After the addition is complete, reflux the mixture for 5 h. Cool the mixture to room temperature and let stand for 2.5 days. Collect the light yellow solid, wash with water and dry in a vacuum oven at 80° C. for 3 h. MS (ES−) 193.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6): δ 11.31 (s, 1H), 7.90 (dd, 1H, J=8.8, 2.2 Hz), 7.76 (d, 1H, J=2.6 Hz), 7.06 (d, 1H, J=8.8 Hz), 4.72 (s, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]O.C1(C)C=CC=CC=1>O>[Cl:3][CH2:22][C:21]1[CH:20]=[C:19]([CH:26]=[CH:25][CH:24]=1)[O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH3:5]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
Thionyl chloride (4.45 ml) was added dropwise to a mixture of 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylalcohol (15.0 g) and toluene (200 ml) at 0° C. After stirring at room temperature for 1 hour, water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (13.4 g, yield 84%) as pale-yellow crystals. m.p. 79-80° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[C:43]([O:44][CH3:45])=[CH:42][C:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[O:34])[CH2:30][CH2:31][C:25]=2[CH:24]=1>>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:22][C:23]2[C:43]([O:44][CH3:45])=[CH:42][C:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]([N:35]4[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]4)=[O:34])[CH2:30][CH2:31][C:25]=3[CH:24]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N1CCN(C)CC1)CC2
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n1)CCN(CC(=O)N1CCN(C)CC1)CC2
Yield: 18 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine and 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-1-(4-methyl-piperazin-1-yl)-ethanone. Product isolated as an off-white foam (20 mg, 18%). mp: 170° C. (glass 105), MS (ESI+): 642.5 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.52 (s, 1H), 8.57 (d, J=8 Hz, 1H), 8.17 (s, 1H), 8.01 (s, 1H), 7.95 (d, J=9 Hz, 1H), 7.62 (t, J=8 Hz, 1H), 7.52 (s, 1H), 7.26 (m, 1H), 6.67 (s, 1H), 5.32 (s, 1H), 3.89 (s, 3H), 3.72 (m, 2H), 3.68 (m, 2H), 3.30 (m, 3H), 2.88 (m, 2H), 2.74 (m, 2H), 2.70 (m, 2H), 2.66 (m, 2H), 2.46 (m, 2H), 2.42 (m, 2H), 2.34 (s, 3H), 1.33 (d, J=7 Hz, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C1(CCCCN)C=CC=CC=1.Cl.[F:62][C:63]1[CH:68]=[CH:67][C:66]([CH:69]([C:74]2[CH:79]=[CH:78][C:77]([F:80])=[CH:76][CH:75]=2)[CH2:70][CH2:71][CH2:72][NH2:73])=[CH:65][CH:64]=1>CN(C=O)C.C(OCC)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:14](=[O:16])[NH:73][CH2:72][CH2:71][CH2:70][CH:69]([C:66]1[CH:65]=[CH:64][C:63]([F:62])=[CH:68][CH:67]=1)[C:74]1[CH:79]=[CH:78][C:77]([F:80])=[CH:76][CH:75]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
N-tert-butoxycarbonyl-L-leucine (0.84 g, 3.4 mmol, Bachem Inc., Torrance, Calif.) was dissolved in dry DMF (7 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (1.8 mL, 10 mmol) and solid O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.3 g, 3.4 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; benzenebutanamine, 4,4-bis-(4-fluoro-phenyl)-butylamine monohydrochloride (1.0 g, 3.4 mmol) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 2% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. Concentration in vacuo followed by drying under vacuum afforded 1.4 g (90%) of the pure titled compound was obtained as a white foam: mp 50-55° C. APCI-MS m/z 475.3 (MH+).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O:21]CC=C)=[O:20])=[C:14]([CH2:17]O)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.[OH:27][CH2:28][C:29]1[S:33][C:32]2=[CH:34][N:35]=[CH:36][N:31]2[C:30]=1[CH3:37]>>[OH:7][C@@H:8]([C@H:10]1[C:25](=[O:26])[N:12]2[C:13]([C:19]([O-:21])=[O:20])=[C:14]([CH2:17][N:35]3[CH:34]=[C:32]4[S:33][C:29]([CH2:28][OH:27])=[C:30]([CH3:37])[N+:31]4=[CH:36]3)[C@H:15]([CH3:16])[C@H:11]12)[CH3:9]
Reactant: Cc1c(CO)sc2cncn12
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Product: Cc1c(CO)sc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 6.4 %

Procedure:
The same procedure as in Example 1 was repeated except that 135 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 186 mg of 2-hydroxymethyl-3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 9.3 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([CH2:22][N:23]3[CH2:33][CH2:32][C:26]4([C:30](=[O:31])[NH:29][CH2:28][CH2:27]4)[CH2:25][CH2:24]3)[N:18]2[CH3:21])=[C:14]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[N:13]=1>>[CH3:21][N:18]1[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]3([C:30](=[O:31])[NH:29][CH2:28][CH2:27]3)[CH2:32][CH2:33]2)=[N:16][C:15]2[C:19]1=[N:20][C:12]([N:3]1[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=[C:2]1[CH3:1])=[N:13][C:14]=2[N:34]1[CH2:35][CH2:36][O:37][CH2:38][CH2:39]1
Reactant: Cn1c(CN2CCC3(CCNC3=O)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CCNC4=O)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-methylbenzimidazole and 8-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-2,8-diazaspiro[4.5]decan-1-one were reacted to give 379. LCMS m/z 258.6 (2M+H+)
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH2:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[F:41][C@@H:42]1[C@H:46]([CH:47]=O)[CH2:45][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:43]1>C(Cl)Cl>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:26][CH2:47][C@H:46]1[C@@H:42]([F:41])[CH2:43][N:44]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:50])[CH2:45]1)[C:22]([CH3:23])([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(N)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Reactant: O=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C(NC[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Reaction time: 0.33 h
Yield: 9.2 %

Procedure:
To a solution of (±)-1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropan-1-amine (240 mg, 0.673 mmol) in CH2Cl2 (5.0 mL) was added NaBH(OAc)3 (2.86 g, 13.5 mmol). To this solution, the crude (3R,4S)-benzyl 3-fluoro-4-formylpyrrolidine-1-carboxylate (obtained from 2.0 equiv. of (3R,4R)-benzyl 3-fluoro-4-vinylpyrrolidine-1-carboxylate) in CH2Cl2 (1.0 mL) was rapidly added at room temperature. After stirred for 20 min, the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified on preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to yield (±)-(3R,4R)-benzyl 3-((1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropylamino)methyl)-4-fluoropyrrolidine-1-carboxylate (37 mg, 9.2%). LC/MS (uplc) MH+ 592.4, 0.91 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1)[C:8](O)=[O:9])[CH3:2].[CH3:36][N:37]1[CH2:42][CH2:41][CH:40]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:39][CH2:38]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[CH2:34][CH3:35])[CH2:6][CH:7]([CH2:11][C:12]([N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:17][CH2:18]1)=[O:30])[C:8]([N:46]1[CH2:47][CH2:48][N:43]([CH:40]2[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]2)[CH2:44][CH2:45]1)=[O:9])[CH3:2]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Product: CCc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-diethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-(1-methyl-piperidin-4-yl)-piperazine.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Solvent: CCCCO
Product: CC(C)(C)OC(=O)NC1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 160 °C
Reaction time: 20 h
Yield: 32.5 %

Procedure:
A solution of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (120 mg, 0.358 mmol) in n-BuOH (5 mL) was treated with tert-butyl piperidin-3-ylcarbamate (359 mg, 1.79 mmol) and stirred at 160° C. for 20 hours in a sealed tube. The mixture was concentrated in vacuo, and the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 20-80% CH3CN/water gradient; 20 CV) to provide tert-butyl 1-(5-bromo-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (60 mg, 32% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ 10.10 (br s, 1H), 9.27 (m, 1H), 9.19 (d, 1H), 8.79 (d, 1H), 8.33-8.29 (m, 2H), 8.18 (br s, 1H), 7.51-7.47 (m, 1H), 4.54-4.78 (m, 1H), 3.84-3.69 (m, 1H), 3.64-3.41 (m, 3H), 3.08-2.95 (m, 1H), 2.09-1.96 (m, 1H), 1.92-1.50 (m, 2H), 1.42 (s, 9H); LCMS (APCI+) m/z 515.1, 517.1 (M+H)+, Retention time=2.83 minutes (Method 1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1nccs1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 67.6 %

Procedure:
Under a N2 atmosphere, a mixture of the 6-chloropyridine-3-sulfonyl chloride (0.95 gm, 4.51 mmol), 2-aminothiazole (0.452 gm, 4.51 mmol), and pyridine (7.0 mL) was stirred at RT for 19 h. The crude product was purified via silica gel chromatography using (2-10%) MeOH in CH2Cl2. After evaporating the solvents under reduced pressure, purification via silica gel chromatography using 2-10% MeOH in CH2Cl2 gave 6-chloro-N-(thiazol-2-yl)pyridine-3-sulfonamide as a white solid (0.841 g, 68%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=276.2; tR=0.6 min.
Reaction SMILES: C(OC([N:8]=[C:9]1[N:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21]([OH:23])=[O:22])[C:12]2[CH:27]=[CH:28][CH:29]=[CH:30][C:11]=2[N:10]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[CH2:43][CH2:42][N:41]([CH2:44][C:45]3[CH2:50][C:49]([CH3:52])([CH3:51])[CH2:48][CH2:47][C:46]=3[C:53]3[CH:58]=[CH:57][C:56]([Cl:59])=[CH:55][CH:54]=3)[CH2:40][CH2:39]2)[CH:33]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:59][C:56]1[CH:55]=[CH:54][C:53]([C:46]2[CH2:47][CH2:48][C:49]([CH3:52])([CH3:51])[CH2:50][C:45]=2[CH2:44][N:41]2[CH2:40][CH2:39][N:38]([C:34]3[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=3)[CH2:31][N:10]3[C:11]4[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=4[N:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([OH:23])=[O:22])[C:9]3=[NH:8])[CH2:43][CH2:42]2)=[CH:58][CH:57]=1
Reactant: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3cccc(Cn4c(=NC(=O)OC(C)(C)C)n(CCCOc5cccc(C(=O)O)c5)c5ccccc54)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3cccc(Cn4c(=N)n(CCCOc5cccc(C(=O)O)c5)c5ccccc54)c3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
To a solution of 3-{3-[2-[tert-butoxycarbonylimino]-3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid (0.15 g, 0.18 mmol) in dichloromethane (2.25 ml) at rt was added TFA (0.75 ml). The reaction was stirred at rt for 1 h and then concentrated under reduced pressure. The crude product was purified by preparative HPLC to provide 3-{3-[3-(3-{4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid (8.5 mg, 6%). HPLC-MS 718 [M+1]+, 360.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:34])([F:33])[O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]([NH:22][C:23]3[CH:28]=[C:27]([F:29])[C:26]([C:30]#[N:31])=[CH:25][C:24]=3[F:32])=[N:20][N:19]=[N:18]2)=[CH:13][CH:12]=1.S(=O)(=O)(O)O>>[F:34][C:9]([F:8])([F:33])[O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]([N:22]([C:1](=[O:3])[CH3:2])[C:23]3[CH:28]=[C:27]([F:29])[C:26]([C:30]#[N:31])=[CH:25][C:24]=3[F:32])=[N:20][N:19]=[N:18]2)=[CH:15][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1cc(F)c(Nc2nnnn2-c2ccc(OC(F)(F)F)cc2)cc1F
Agent: O=S(=O)(O)O
Product: CC(=O)N(c1cc(F)c(C#N)cc1F)c1nnnn1-c1ccc(OC(F)(F)F)cc1

Procedure:
A mixed solution of acetic anhydride (15 ml), 1-(4-trifluoromethoxyphenyl)-5-(4-cyano-2,5-difluoroanilino)tetrazole (1.5 g) and concentrated sulfuric acid (1 ml) was stirred at 70 to 80° C. for 1 hour. After unreacted acetic anhydride was distilled off under reduced pressure, the residue was washed with water and n-hexane to obtain 1-(4-trifluoromethoxyphenyl)-5-(4-cyano-2,5-difluoro-N-acetylanilino)tetrazole (1.55 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:9][N:8](C3CCCCO3)[C:5]2=[CH:6][N:7]=1.[NH:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CNCCNC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu]I>[N:23]1([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[N:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: c1c[nH]cn1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc(-c2n[nH]c3cnc(-n4ccnc4)cc23)cc1
Temperature: 120 °C

Procedure:
A mixture of 100.0 mg (0.2791 mmol) of 5-bromo-3-phenyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine, 47.51 mg (0.6979 mmol) of 1H-Imidazole, 53.16 mg (0.2791 mmol) of Copper(I) iodide, 30.04 uL (0.2791 mmol) of N,N′-dimethylethylenediamine and 363.8 mg (1.116 mmol) of Cesium Carbonate in 3 ml of N,N-Dimethylformamide was heated at 120° C. for 48 hours. The mixture was filtered, the filtrate concentrated in high vacuum and the residue partitioned between ethyl acetate and water. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated in vacuum. The residue was purified on 4 g of silica gel column, eluting 5-(1H-imidazol-1-yl)-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine with a gradient of ethyl acetate in heptane. Yield 67 mg (69%). ESI MS m/z 346.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:16])(=O)[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]>>[C:5]([Cl:3])(=[O:16])[CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCOCCOCC(=O)O
Reactant: O=S(Cl)Cl
Product: COCCOCCOCC(=O)Cl
Reaction time: 0.75 h

Procedure:
Thionyl chloride, 8.0 grams (0.112 mole) was stirred, and 10.0 grams (0.056 mole) of 3,6,9-trioxadecanoic acid was added dropwise during a 45 minute period. Upon completion of addition, the reaction mixture was warmed to reflux where it stirred for 45 minutes. The reaction mixture was cooled, yielding 3,6,9-trioxadecanoyl chloride. An 80% yield of acid chloride was assumed.