Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]([N+:24]([O-:26])=[O:25])=[C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:9]=1>O.C(O)C>[CH2:17]([O:16][C:14]([C:13]1[C:8]([S:1]([OH:4])(=[O:3])=[O:2])=[N:9][C:10]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:11]([N+:24]([O-:26])=[O:25])[C:12]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(S(=O)(=O)O)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Yield: 59.9 %

Procedure:
A solution of 0.28 g of sodium sulfite in 7 ml of water was added to a solution of 0.70 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine in 7 ml of ethanol, and the mixture was heated under reflux for minutes. After the reaction mixture was concentrated, the concentrate was acidified with 1N HCl, followed by extraction with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. After concentration to dryness under reduced pressure, the residue was recrystallized from chloroform/ether, to give 0.47 g of white crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]=[C:6]([CH3:8])[N:5]([CH2:9][C:10]([OH:12])=O)[N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:5]1[C:6]([CH3:8])=[N:7][C:3]([CH3:2])=[N:4]1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1nc(C)n(CC(=O)O)n1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: Cc1nc(C)n(CC(=O)N[C@@H](COCc2ccccc2)C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 27 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 256, (S)-3-(benzyloxy)-2-(2-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (219 mg, 27%). 1H-NMR (400 MHz, CDCl3): σ 8.38 (s, 1H), 7.40-7.16 (m, 7H), 7.05-6.92 (m, 5H), 4.74 (s, 2H), 4.70-4.64 (m, 3H), 4.55 (d, 1H), 4.02-3.97 (m, 1H), 3.62-3.56 (m, 1H), 2.44 (s, 3H), 2.33 (s, 3H). MS (EI) for C28H28FN5O4. found 518.0 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[C:14](#N)[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17].Cl.C1C[O:27]CC1>C(OCC)(=O)C>[NH2:17][C:16]1[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=1[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1)=[O:27]
Reactant: C1CCOC1
Reactant: Fc1cccc(Br)c1
Reactant: N#Cc1ccccc1N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromofluorobenzene (1 eq.) in THF was cooled to −78° C. under nitrogen and treated with tert-butyllithium (2.05 eq., 1.6 M solution in pentane) at a rate of 40 mL/h. The internal temperature did not rise above −74° C. The orange solution was stirred at −78° C. for 30 minutes prior to the addition of anthranilonitrile (0.6 eq.) as a solution in THF. The reaction was warmed to 0° C. and stirred for 2 hours. 3N HCl was added to the mixture and stirring continued for 30. minutes. The reaction was diluted with ethyl acetate and the layers were separated. The aqueous layer was back-extracted thrice with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified via HPLC eluting with 93:7 hexanes/ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[F:44][C:45]1[CH:50]=[CH:49][C:48]([CH:51]([NH2:53])[CH3:52])=[CH:47][CH:46]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:53][CH:51]([C:48]2[CH:49]=[CH:50][C:45]([F:44])=[CH:46][CH:47]=2)[CH3:52])=[O:42])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(N)c1ccc(F)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ccc(F)cc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (81 mg) was dissolved in chloroform (2 ml) and triethylamine (0.2 ml) to prepare a solution. A solution of triphosgene (70 mg) in chloroform (0.4 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(4-fluorophenyl)ethylamine (70 mg) in chloroform (0.4 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (6 mg, yield 5%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=[N:29]2)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[C:32]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]5[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=5)=[CH:9][N:10]=4)[CH:7]=3)=[CH:31][CH:30]=[N:29]2)=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Product: CS(=O)(=O)c1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, white solid (84 mg, 66%), MS (ISP) m/z=449.6 [(M+H)+], mp 259° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-methanesulfonyl-phenyl)-imidazo[1,2-a]pyridine (intermediate O) (0.1 g, 0.285 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.11 g, 0.37 mmol).
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].[CH2:14]([O:21][C:22](=[O:28])[NH:23][CH2:24][C@H:25]1[CH2:27][O:26]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:27][C@@H:25]([OH:26])[CH2:24][NH:23][C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:28])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NC[C@H]1CO1)OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CNC(=O)OCc2ccccc2)CC1
Yield: 37 %

Procedure:
The compound was prepared in analogy to Example 17, step 17.1, starting from 1-Boc-piperazine (20.41 g) and [(2S)-oxiranylmethyl]-carbamic acid benzyl ester (22.75 g). A yellowish oil (16.0 g; 37% yield) was obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH:10]([CH2:16][O:17][C:18]2[N:19]=[N:20][C:21]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)=[CH:26][CH:25]=3)[CH:23]=2)[CH2:9]1)=O)(C)(C)C.[ClH:41]>O1CCOCC1.C(Cl)Cl>[ClH:41].[ClH:41].[CH2:37]([C:21]1[N:20]=[N:19][C:18]([O:17][CH2:16][CH:10]2[C:11]([F:15])([F:14])[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9]2)=[CH:23][C:22]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)=[CH:26][CH:25]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCc1nnc(OCC2CN(C(=O)OC(C)(C)C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OCC2CN(C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 50 °C

Procedure:
A mixture of 3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4,4-difluoro-piperidine-1-carboxylic acid tert-butyl ester (0.36 mmol, 0.2 g) and 4M HCl in dioxane solution (3 mL) in 10 mL of DCM was heated at 50° C. for 1 h. Removed the solvent afforded the crude 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-piperidin-3-ylmethoxy)-pyridazine dihydrochloride as a yellowish solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+]([O-])=O)[CH:6]=[CH:5][N:4]=1)[CH3:2].[OH-].[Na+].C([Br:17])(=O)C>>[Br:17][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: CC(=O)Br
Reactant: CCc1cc([N+](=O)[O-])ccn1
Agent: [Na+]
Agent: [OH-]
Product: CCc1cc(Br)ccn1
Temperature: 75 °C
Yield: 62 %

Procedure:
A mixture of 2-ethyl-4-nitro-pyridine (2.3 g, 15.1 mmol) and acetyl bromide (9 mL) were heated together at 75° C. for 16 hours. More acetyl bromide (10 mL) was added and the reaction was heated to 100° C. for 5 hrs. The reaction mixture was poured into ice, made basic with 20% NaOH and extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4 and concentrated to a black oil. Purification by flash silica gel chromatography (0% to 25% EtOAc) gave the product as an oil (1.72 g, 62%). 1H NMR (400 MHz, CDCl3): δ 1.30 (t, J=7.6 Hz, 3H), 2.81 (d, J=7.6 Hz, 2H), 7.28 (dd, J=5.3, 1.8 Hz, 1H), 7.35 (d, J=1.8 Hz, 1H), 8.34 (d, J=5.3 Hz, 1H).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH2:29]O)[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:55]I>C1COCC1.CCOC(C)=O>[C:1]12([C:11]3[CH:12]=[C:13]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[CH:25]=[C:24]([CH2:29][I:55])[CH:23]=[CH:22]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: II
Reactant: COc1ccc(-c2ccc3cc(CO)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc3cc(CI)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2
Yield: 44.9 %

Procedure:
To a solution of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyl alcohol (0.365 g, 0.92 mmol), triphenylphosphine (0.366 g, 1.39 mmol) and imidazole (0.095 g, 1.39 mmol) in 7 mL of anhydrous THF at 0° C. was added dropwise a solution of I2 (0.303 g, 1.19 mmol) in 4 mL of anhydrous THF. After 30 minutes the mixture was diluted with EtOAc and washed with sodium thiosulfate aq. (100 mL), brine (100 mL), dried with magnesium sulfate, filtered and evaporated. The residue was purified on silica gel (eluent: hexane:EtOAc 100 to 95:5) to give 0.210 g of 6-[3-(1-adamantyl)-4-methoxyphenyl]-naphthalen-2-yl-methyliodide (45%). 1H NMR (300 MHz; CDCl3): δ 1.80 (s, 6H), 2.10–2.18 (m, 9H), 3.89 (s, 3H), 4.65 (s, 2H), 6.98 (d, J=8.7 Hz, 1H), 7.46–7.57 (m, 3H), 7.71–7.93(m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:27][C:28](Br)=[O:29].[NH2:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=2)[CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:27][C:28]([NH:31][CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=2)[CH2:34][CH2:33]1)=[O:29]
Reactant: O=C(Br)CBr
Reactant: COc1ccc2c(c1)C(N)CC2
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)cc32)cc1OC
Product: COc1ccc2c(c1)C(NC(=O)CN1CCc3cc(OC)c(OC)cc3C1Cc1ccc(OC)c(OC)c1)CC2

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1-amino-6-methoxy-indane
Reaction SMILES: C([O:8][C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][C@H:24]([C:28]([N:30]2[CH2:47][CH2:46][CH2:45][C@H:31]2[C:32]([NH:34][CH:35]([CH:42]([CH3:44])[CH3:43])[C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[O:33])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:17][CH:16]=1)=[O:14])=[O:10])C1C=CC=CC=1.[H][H]>CO.O.[Pd]>[C:9]([CH2:11][NH:12][C:13]([C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][C@H:24]([C:28]([N:30]2[CH2:47][CH2:46][CH2:45][C@H:31]2[C:32]([NH:34][CH:35]([CH:42]([CH3:43])[CH3:44])[C:36](=[O:41])[C:37]([F:39])([F:40])[F:38])=[O:33])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])=[CH:19][CH:20]=1)=[O:14])([OH:10])=[O:8]
Reactant: [H][H]
Reactant: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)OCc2ccccc2)cc1)C(C)C)C(=O)C(F)(F)F
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(C)C(NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)c1ccc(C(=O)NCC(=O)O)cc1)C(C)C)C(=O)C(F)(F)F
Yield: 100.9 %

Procedure:
A solution of 3(RS)-[[4-[(benzyloxycarbonyl)methylaminocarbonyl]phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (70 mg) in a mixture of methanol (10 ml) and water (1 ml) was hydrogenated over 10% palladium on carbon (1.0 g) at 3 atmosphere pressure of hydrogen for 3 hours at room temperature. After the catalyst was removed by filtration, the filtrate was evaporated under reduced pressure to give 3(RS)-[[4-(carboxymethylaminocarbonyl)phenylcarbonyl]-L-valyl-L-prolyl]amino-1,1,1-trifluoro-4-methyl-2-oxopentane (61 mg).
Reaction SMILES: [CH3:1][N:2]1[O:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[N:5](C(OCC)=O)[CH2:6]2>O>[CH3:1][N:2]1[O:9][CH2:8][CH:7]2[CH:3]1[CH:4]([CH3:15])[NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2CON(C)C2C1C
Solvent: O
Product: CC1NCC2CON(C)C21

Procedure:
9.2 g (42.9 mmol) of ethyl 2,8-dimethyl-3-oxa-2,7-diazabicyclo[3.3.01octane-7-carboxylate are heated under reflhx with 23.5 g of Ba(OH)2 ·8H2O in 235 ml of water overnight. The BaCO3 is filtered off with suction, K2CO3 is added to the filtrate and the solid is filtered off with suction again. The filtrate is extracted ten times with 50 ml of CHCl3 each time, the extracts are dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:7]([CH3:8])[O:6][CH2:5][C:4](=[O:9])[CH:3]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O.[C:20]([O:26][CH3:27])(=[O:25])[CH2:21][C:22]([CH3:24])=O>C(O)C>[Br:10][C:11]1[CH:12]=[C:13]([CH:14]2[C:21]([C:20]([O:26][CH3:27])=[O:25])=[C:22]([CH3:24])[NH:1][C:2]3[CH:7]([CH3:8])[O:6][CH2:5][C:4](=[O:9])[C:3]2=3)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: COC(=O)CC(C)=O
Reactant: CC1OCC(=O)C=C1N
Solvent: CCO
Product: COC(=O)C1=C(C)NC2=C(C(=O)COC2C)C1c1ccc(F)c(Br)c1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
The product from Example 88D (0.50 g, 3.9 mmol), 3-bromo-4-fluorobenzaldehyde 0.96 g, 4.7 mmol) and methyl acetoacetate (0.46 g, 3.9 mmol) in ethanol (4 mL) was heated to 80° C. in a sealed tube for 60 hours, cooled to ambient temperature and concentrated. The residue was chromatographed on silica gel eluting with 1% and then 2% methanol in dichloromethane to provide the title compound (0.97 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.I[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[N:13]([CH:21]([CH3:23])[CH3:22])[N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]([N:13]1[C:14]2=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]2[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:12]1)([CH3:23])[CH3:22]
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2cccnc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of 3-Pyridinylboronic acid (15 mg, 0.14 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (40 mg, 0.13 mmol) in DME (12 ml). Pd(PPh3)4 (15 mg, 0.015 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA52. ESI-MS (M+H)+ m/z calcd 255.1, found 255.0.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>CN(C)P(N(C)C)(N(C)C)=O>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: OCCCCCCCCCCCCCCCCBr
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(NCCCCCCCCCCCCCCCCO)cc1
Temperature: 120 °C

Procedure:
p-Aminobenzonitrile (12 g.) and 16-bromo-1-hexadecanol (15 g.) are dissolved in hexamethylphosphoramide (200 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water (50 ml.) is added gradually. The mixture is then chilled in an ice-bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. The pale brownish yellow granular solid is obtained as a homogeneous product. Recrystallization from ether-hexane affords 4-(16-hydroxyhexadecylamino)benzonitrile as pale yellow prisms.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:9])[CH3:8].Br[CH2:29][C:30]1[C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:33]([C:51]([F:54])([F:53])[F:52])=[CH:32][CH:31]=1.O>CN(C)C=O>[C:7]([C:10]1[CH:15]=[C:14]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:13]=[CH:12][C:11]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:29][C:30]2[C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[C:34]([O:43][C:44]([O:46][C:47]([CH3:49])([CH3:48])[CH3:50])=[O:45])[C:33]([C:51]([F:52])([F:53])[F:54])=[CH:32][CH:31]=2)=[CH:23][CH:22]=1)(=[O:9])[CH3:8]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)=O)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.9 %

Procedure:
Cesium carbonate (209 mg, 0.644 mmol) was added to a solution of methyl (2-acetyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (122 mg, 0.429 mmol) obtained in Example (40-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (181 mg, 0.429 mmol) obtained in Example (28-5) in N,N-dimethylformamide (4 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate (three times). After the organic layer was successively washed with water (three times) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate, it was concentrated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: hexane/ethyl acetate=3/1) to give tert-butyl 6-[({2′-acetyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (93 mg, yield: 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([N:20]4[CH2:25][CH:24]([CH3:26])[N:23]([C:27](=[O:29])[CH3:28])[CH:22]([CH3:30])[CH2:21]4)[CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.C(Cl)Cl.CCN(C(C)C)C(C)C.[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48](Cl)=[O:49]>CN1C(=O)CCC1>[C:27]([N:23]1[CH:24]([CH3:26])[CH2:25][N:20]([C:16]2[CH:15]=[C:14]([N:11]3[CH:12]=[N:13][C:9]([NH:8][C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:48]([C:44]5[O:43][CH:47]=[CH:46][CH:45]=5)=[O:49])=[CH:3][CH:4]=4)=[N:10]3)[CH:19]=[CH:18][N:17]=2)[CH2:21][CH:22]1[CH3:30])(=[O:29])[CH3:28]
Reactant: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(N)cc4)n3)ccn2)CC1C
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(=O)N1C(C)CN(c2cc(-n3cnc(Nc4ccc(NC(=O)c5ccco5)cc4)n3)ccn2)CC1C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
To a solution of 50 mg of 1-(4-{4-[3-(4-Amino-phenylamino)-[1,2,4]triazol-1-yl]-pyridin-2-yl}-2,6-dimethyl-piperazin-1-yl)-ethanone (0.123 mMol. 1.00 equiv) in 2 mL of NMP was added 5 mL of CH2Cl2 and 500 μL of Hunig's base followed by 100 μL of 2-furanoyl chloride (1.01 mMol, 8.13 equiv). The reaction mixture was stirred for 1 hr and concentrated. The resulting oil was purified via flash chromatography (EtOAc) to yield 1.4 mg of Furan-2-carboxylic acid (4-{1-[2-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-1H-[1,2,4]triazol-3-ylamino}-phenyl)-amide (0.0028 mMol, 2.3% yield). 1H NMR (500 MHz, MeOD-d4) ∂ 8.95 (1H, s), 8.18 (1H, d), 7.72 (1H, m), 7.61 (4H, m), 7.25 (2H, m), 7.15 (1H, m), 6.61 (1H, s), 4.30 (2H, m), 3.30 (2H, m), 3.15 (2H, m), 2.20 (3H, s), 1.35 (6H, m) ppm. LC/MS: 2.2 min/501.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([O:10][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=2)(=[O:32])=[O:31])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 88.4 %

Procedure:
To a solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (10 g, 40.77 mmol) in methylene chloride (56 mL) at 0° C. was added pyridine (30 mL), followed by dropwise addition of a solution of p-toluenesulfonyl chloride (9.4 g, 49.30 mmol) in methylene chloride. The reaction mixture was warmed to room temperature and then refluxed for 16 h. The reaction mixture was concentrated, re-dissolved in methylene chloride, and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-4-(toluene-4-sulfonyloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (14.4 g, 88.4% yield) as a light yellow sticky solid. The crude was used in the next step without further purification. MS calcd. for C18H26NO7S [(M+H)+] 400.0, obsd. 400.0.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OCCCCO
Solvent: c1ccncc1
Product: O=C(OCCCCO)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of 1,4-butanediol (18 ml, 0.2 mmol) in pyridine (16 ml), was added slowly at 0° C., under a nitrogen atmosphere, benzoyl chloride (1 ml), 0.1 mmol). After 4 h under stirring at 0° C., the reaction medium was concentrated and the pyridine was eliminated by co-distillation with toluene. The residue was extracted with ether (3×20 ml) and the organic phase was dried (magnesium sulfate), concentrated, and subjected to a flash column chromatography on silica gel (petroleum ether/ethyl acetate 3:2) to give the 4-hydroxybutyl benzoate (9.9 g, 55%) in the form of a colorless oil.