Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41])[CH3:9]
Reactant: C[C@H](N)c1ccccc1F
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccccc3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-fluorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 521 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[NH2:7])#[N:3].[N:16]([O-])=O.[Na+]>>[C:2]([C:4]1[CH:5]=[C:6]([NH:7][NH2:16])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH:13]([CH3:15])[CH3:14])#[N:3]
Reactant: CC(C)COc1ccc(N)cc1C#N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)COc1ccc(NN)cc1C#N
Yield: 82.8 %

Procedure:
To an aqueous solution (34 ml) of 3-cyano-4-isobutoxyaniline hydrochloride (20 g) were added sodium nitrite (6.8 g), stannous chloride dihydrate (61 g) and con. hydrochloric add (100 ml) with stirring under ice-cooling. After the completion of the reaction, precipitated crystals were collected by filtration. The crystals were added to water, and the mixture was neutralized with aqueous sodium hydroxide solution, extracted with a mixed solvent of toluene and tert-butanol, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 15 g of 3-cyano-4-isobutoxy-phenylhydrazine.
Reaction SMILES: [CH:1](=[N:8]/[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19](O)(=[O:21])[CH3:20]>>[CH2:1]([N:8]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[CH:10]=1)[C:19](=[O:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Oc1ccc(/N=C/c2ccccc2)cc1F
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(Cc1ccccc1)c1ccc(O)c(F)c1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a stirred solution of (E)-4-(benzylideneamino)-2-fluorophenol (430 mg, 2 mmol) in 1 mL glacial acetic acid at 0° C. under nitrogen was added a solution of trimethylamine/borane complex (160 mg, 2.2 mmol) in 1 mL glacial acetic acid dropwise by syringe. After complete addition, the reaction was allowed to warm to room temperature and was then heated to reflux overnight. 6N NaOH was then added until pH was neutral. The aqueous solution was extracted with ether, and the combined ether extracts were dried (MgSO4), filtered and concentrated. The material was loaded onto a Biotage 40S column with dichloromethane and eluted with 4/1 hexanes/EtOAc to afford the product as a white solid (200 mg, 39% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH2:25])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:8][CH:7]=1.[Cl:27][C:28]1[CH:29]=[CH:30][C:31]([NH2:37])=[C:32]([CH:36]=1)[C:33](O)=[O:34]>>[CH3:1][O:2][C:3](=[O:26])[C@@H:4]([NH:25][C:33](=[O:34])[C:32]1[CH:36]=[C:28]([Cl:27])[CH:29]=[CH:30][C:31]=1[NH2:37])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:11]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N

Procedure:
(2S)-(2-Amino-5-chloro-benzoylamino)-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester was prepared (0.6 g, 80%) from (2S)-Amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (0.5 g, 1.5 mmol), 5-chloro-2-amino-benzoic acid (0.28 g, 1.65 mmol) as desribed in general procedure A.
Reaction SMILES: [H-].[Na+].C(S)C.[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:17]C)[CH:8]=1>CN(C)C=O>[NH2:6][C:7]1[C:15]([Cl:16])=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[C:9]([OH:17])[CH:8]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Product: Nc1cc(O)c(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.4 %

Procedure:
A cooled (5° C.) suspension of 60% sodium hydride/oil dispersion (20.0 g, 0.50 mole) in anhydrous dimethylformamide (300 mL) under nitrogen was treated slowly dropwise with ethyl mercaptan (18.7 g, 0.30 mole) so as to maintain a pot temperature below 15° C., then stirred at room temperature for 15 minutes, cooled (5° C.), and treated in portions with 4-amino-5-chloro-2-methoxybenzoic acid (40.33 g, 0.20 mole). The mixture was heated to 105±5° C. for 4 hours, cooled, and concentrated in vacuo to remove most of the dimethylformamide, then plunged into water (500 mL). The aqueous solution was extracted with methylene chloride (2×150 mL), and ether (150 mL), acidified with concentrated HCl (55 mL), filtered, and the filter cake washed with water and dried in vacuo to afford 35.7 g of crude product. Crystallization from tetrahydrofuran/hexane afforded 31.3 g (83%) of white solid; mp 192° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21](Br)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:17]([CH:18]3[CH2:20][CH2:19]3)[C:16]3[C:21]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)=[C:22]([F:25])[CH:23]=[CH:24][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(Br)c2n1C1CC1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c(-c3cccnc3)c2n1C1CC1
Temperature: 140 °C
Yield: 43.7 %

Procedure:
A mixture of 4-amino-6-[(S)-1-(7-bromo-1-cyclopropyl-6-fluoro-1H-benzoimidazol-2-yl)ethylamino]pyrimidine-5-carbonitrile (68 mg, 0.16 mmol), pyridine-3-boronic acid (26 mg, 0.21 mmol), tetrakis(triphenylphosphine)palladium (19 mg, 10 mol %) and caesium carbonate (106 mg, 0.33 mol) in dioxane (3 mL) and H2O (1.5 mL) was purged with argon gas then heated at 140° C., for 30 min, by microwave irradiation. After cooling to RT, the reaction mixture was diluted with MeOH and loaded into an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a gradient 10-90%, 0.1% NH4OH in acetonitrile/water) to afford 414 as a white solid (29 mg, 43%). LCMS (Method K): RT 2.80 min [M+H]+ 415.06. 1H NMR (CDCl3 400 MHz): δ 8.74 (1H, s), 8.66 (1H, dd, J=4.86, 1.69 Hz), 8.17 (1H, s), 7.86 (1H, s), 7.70 (1H, dd, J=8.79, 4.66 Hz), 7.43 (1H, dd, J=7.83, 4.85 Hz), 7.13 (1H, dd, J=10.24, 8.78 Hz), 6.45-6.14 (1H, br m), 5.97 (1H, m), 5.36 (2H, s), 2.95 (1H, m), 1.70 (3H, d, J=6.73 Hz), 1.02-0.09 (4H, m)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:14]([F:17])([F:16])[F:15])[CH2:9][C:10](OC)=[O:11])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:19].C(O)(C)C>>[Cl:1][C:2]1[C:7]2[CH:8]([C:14]([F:17])([F:16])[F:15])[CH2:9][C:10](=[O:11])[NH:19][C:6]=2[N:5]=[CH:4][N:3]=1
Reactant: COC(=O)CC(c1c(Cl)ncnc1Cl)C(F)(F)F
Reactant: N
Solvent: CC(C)O
Product: O=C1CC(C(F)(F)F)c2c(Cl)ncnc2N1
Temperature: 120 °C
Yield: 83 %

Procedure:
Combine methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate (501.0 g, 1.57 mol) and 2 M ammonia in isopropyl alcohol (1.57 L, 2.0 eq) in a pressure reactor. Heat at 120° C. for seven hours. Cool the mixture to room temperature, then concentrate in vacuo. Dilute with hexanes (1 L). Filter to give crude product. Triturate this solid with 10% isopropyl alcohol in water (600 mL) and water (1.3 L). Filter and dry at 70° C. to give 4-chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (328.9 g, 83%) as a racemate. MS (ES) m/z=252 [M]+.
Reaction SMILES: [ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[ClH:1].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: BrCC1CC1
Agent: Cl
Product: O=C1N(CC2CC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 214° C. and MS: m/e=424.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and bromomethylcyclopropane.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][O:11]1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[O:11]1[CH2:12][CH2:13][O:14][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20]
Reactant: BrCCCCCCCCC1OCCO1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCCCCCCCC2OCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 80.7 %

Procedure:
To a stirred solution of 2-(8-bromooctyl)-1,3-dioxolane (5 g, 18.85 mmol) in dimethyl formamide (100 mL) was added 3-hydroxybenzaldehyde (2.37 g, 19.42 mmol) and potassium carbonate (5.37 g, 38.83 mmol). The reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 0-100% ethyl acetate in iso-hexane to afford the title compound (4.66 g, 78%).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[OH-].[Na+].[Br:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=1)[CH2:13][N:14]=[N+:15]=[N-:16].C(O)(=O)C>C(O)C>[NH2:2][C:1]1[N:14]([CH2:13][C:12]2[CH:17]=[C:18]([C:20]([Cl:24])=[C:21]([Cl:23])[Cl:22])[CH:19]=[C:10]([Br:9])[CH:11]=2)[N:15]=[N:16][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: N#CCC(N)=O
Reactant: [N-]=[N+]=NCc1cc(Br)cc(C(Cl)=C(Cl)Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)c1nnn(Cc2cc(Br)cc(C(Cl)=C(Cl)Cl)c2)c1N
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 36.7 %

Procedure:
To a hot (60° C.) solution of cyanoacetamide (546 mg) in 20 ml of ethanol, 6.47 ml of a methanolic solution of NaOH (1N) was added and the resulting mixture was stirred at 60° C. for 20 minutes. A solution of 3-bromo-5-(trichlorovinyl)benzyl azide (1.02 g) in 10 ml of ethanol was added and the reaction mixture heated at 60° C. for two hours. The pH of the solution was adjusted to ~6 with acetic acid and then concentrated to a small volume. Dilution with 50 ml of water afforded a precipitate which was washed thoroughly with water. The precipitate was recrystallized from 8 ml of ethanol to give 466 mg of pure product, m.p. 175°-177° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[CH3:24][NH2:25]>CO>[CH3:24][NH:25][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1
Reactant: CN
Reactant: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1
Solvent: CO
Product: CNc1cc(C(F)(F)F)cc2nc(NC(=O)c3cccnc3)nn12

Procedure:
The title compound was prepared following procedure and work up described for example 85 but starting from N-[5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]nicotinamide ((B7), 50 mg; 0.15 mmol; 1.0 eq.) and methylamine (1.46 mL of a 2M solution in MeOH; 0.73 mmol; 5.0 eq.) as a white solid (15 mg, 30%). HPLC, Rt: 2.47 min. (purity 96.6%). LC/MS, M+(ESI): 337.0, M−(ESI): 335.0.
Reaction SMILES: CS(O)(=O)=O.CC(O[CH2:10][C:11]1[CH2:20][S:19][C@@H:14]2[C@H:15]([NH2:18])[C:16](=[O:17])[N:13]2[C:12]=1[C:21]([OH:23])=[O:22])=O.[C:24]([NH:27][N:28]1[C:32]([SH:33])=[N:31][N:30]=[N:29]1)(=[O:26])[CH3:25].[OH-].[NH4+]>C(#N)C.O>[NH2:18][C@@H:15]1[C:16](=[O:17])[N:13]2[C:12]([C:21]([OH:23])=[O:22])=[C:11]([CH2:10][S:33][C:32]3[N:28]([NH:27][C:24](=[O:26])[CH3:25])[N:29]=[N:30][N:31]=3)[CH2:20][S:19][C@H:14]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)Nn1nnnc1S
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 75.4 %

Procedure:
Methanesulfonic acid (5.77 g, 60 mmol) was added dropwise to a solution of 7β-aminocephalosporanic acid (3.27 g, 12.0 mmol) and 1-acetamido-5-mercapto-1H-tetrazole (2.50 g, 15.7 mmol) in acetonitrile (15 ml). The mixture was stirred at room temperature for 30 minutes and at 50° C. for 4 hours. Water (20 ml) was added with cooling to the reaction mixture, which was then adjusted to pH 3.5 with 28% aqueous ammonium hydroxide. Precipitates formed were filtered, washed with water and acetone successively and dried to give pale brown powder of 7β-amino-3-[(1-acetamido-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.36 g, 75. 3%), mp~195° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([O:15][CH3:16])[NH:14][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:17]>CO>[CH3:16][O:15][C:13]1[NH:14][C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:17])[C:11]=2[N:12]=1
Reactant: COc1nc2c(Cl)nc3ccccc3c2[nH]1
Reactant: N
Solvent: CO
Product: COc1nc2c(N)nc3ccccc3c2[nH]1
Temperature: 150 °C

Procedure:
4-Chloro-2-methoxy-1H-imidazo[4,5-c]quinoline (700 mg) was added to a high-pressure vessel with ammonia (40 mL of a 7 N solution in methanol), and the vessel was sealed and heated at 150° C. for 24 hours, and then allowed to cool. The contents were concentrated under reduced pressure. The crude product was purified twice by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane first in a gradient from 0:0:100 to 0.3:4.7:95 and secondly in a gradient from 0:0:100 to 0.2:3.8:96) to provide 20 mg of 2-methoxy-1H-imidazo[4,5-c]quinolin-4-amine as a white solid. The compound was further purified by prep HPLC according to the method described in Examples 8-55. The observed accurate mass (M+H) for the isolated trifluoroacetate salt was 215.0931.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: Oc1ccccn1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccn2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and pyridin-2-ol via the same procedure used for the preparation of (2S)-2-Methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1); to produce a colorless oil. MS (ES) for C17H19NO5 [M+H]+: 318.3.
Reaction SMILES: C(OC[C:10]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[N:22]=[C:23]([NH:30][CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=2)=[CH:16][CH:15]=1)[CH3:13])=[O:11])C1C=CC=CC=1.C[CH2:36][OH:37]>[Pd]>[CH:31]1([NH:30][C:23]2[C:24]3[CH:29]=[CH:28][NH:27][C:25]=3[N:26]=[C:21]([NH:20][C:17]3[CH:16]=[CH:15][C:14]([N:12]([CH3:13])[C:10](=[O:11])[O:37][CH3:36])=[CH:19][CH:18]=3)[N:22]=2)[CH2:32][CH2:33][CH2:34]1
Reactant: CN(C(=O)COCc1ccccc1)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Reactant: CCO
Agent: [Pd]
Product: COC(=O)N(C)c1ccc(Nc2nc(NC3CCC3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-benzyloxy N-(4-(4-(cyclobutylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-N-methylacetamide (0.012 g, 0.026 mmol) in EtOH (0.4 mL) was added Pd/C (10 mg), and was charged with H2 (1 atm). After stirring for 15 h at room temperature, it was purified by preparative HPLC to give N-(4-(4-(cyclobutyllamino)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)-2-hydroxy-N-methylacetamide (MS calcd for C19H22N6O2 366.2, found [MH] 367.0; UV 208.7, 272.4, 304.5 nm).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:35]C(=O)OC(C)(C)C)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)=[CH:22][N:21]=[C:20]4[NH:32][CH:33]=[CH:34][C:19]=34)[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:35][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)=[CH:22][N:21]=[C:20]3[NH:32][CH:33]=[CH:34][C:19]=23)[CH2:14][CH2:13]1)=[O:11]
Reactant: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@@H](Cc3ccc(Cl)cc3)NC(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](N)Cc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
(R)-tert-Butyl 3-(4-chlorophenyl)-1-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-1-oxopropan-2-ylcarbamate (0.021 g, 0.036 mmol) was placed in DCM (3 mL) at room temperature. TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-(3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.015 g, 86% yield) as the dihydrochloride salt. MS ESI (+) m/z 491 detected.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.CCN(CC)CC>CN(C=O)C.[Pd]>[CH3:17][O:16][C:14](=[O:15])[CH:13]=[CH:12][C:8]1[C:9]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)nc1Cl
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccc(C(C)(C)C)nc1N1CCOCC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 22.5 %

Procedure:
3-(6-tert-Butyl-2-chloro-pyridin-3-yl)-acrylic acid, methyl ester (0.28 μg, 1.11 mmol) was dissolved in DMF, and morpholine (0.15 ml), NEt3 (0.31 ml) and palladium reagent (48 mg) were added stepwise and then the reaction mixture was stirred at 80° C. for 18 hours. The resulting mixture was extracted with EtOAc, and the organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=8/1) to give 3-(6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl)-acrylic acid methyl ester (76 mg, 0.25 mmol, 22.5%). The methyl ester was dissolved in 1,4-dioxane, treated with water and KOH, stirred and heated at reflux for 18 hrs. The reaction mixture was cooled to room temperature, diluted with water, and then washed with ether. The aqueous phase was acidified with 1N HCl, and then extracted with EtOAc, and the combined organic phase was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure to give 3-(6-tert-butyl-2-morpholin-4-yl-pyridin-3-yl)-acrylic acid (67 mg, 92%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[CH3:26][C:27]1[CH:32]=[C:31]([CH2:33][NH:34][S:35]([C:38]2[S:39][C:40](Br)=[CH:41][CH:42]=2)(=[O:37])=[O:36])[CH:30]=[C:29]([CH3:44])[N:28]=1>>[CH3:26][C:27]1[CH:32]=[C:31]([CH2:33][NH:34][S:35]([C:38]2[S:39][C:40]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=5)=[N:8][C:7]=34)=[CH:41][CH:42]=2)(=[O:36])=[O:37])[CH:30]=[C:29]([CH3:44])[N:28]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1cc(CNS(=O)(=O)c2ccc(Br)s2)cc(C)n1
Product: Cc1cc(CNS(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)s2)cc(C)n1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-bromo-thiophene-2-sulfonic acid (2,6-dimethyl-pyridin-4-ylmethyl)-amide (example B.58) (181 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (120 mg, 38%). MS (ISN) 634.0 [(M−H)−]; mp 200° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.Cl[Pd]Cl>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([S:35]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)(=[O:36])=[O:37])=[CH:39][CH:40]=3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (200 mg, 0.504 mmol), 4-[(4-methyl-1-piperazinyl)sulfonyl]phenylboronic acid (186 mg, 0.655 mmol), PdCl2 (dppf) (29 mg, 0.0355 mmol), and aq. K2CO3 (2M, 3 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 1 hr. The mixture was cooled to room temperature and diluted with H2O, and the aqueous phase extracted with CH2Cl2 (9×). The combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on alumina, eluting with CH2Cl2/MeOH (100:0 to 99.75:0.25), followed by chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), and recrystallization from CH2Cl2/MeOH/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (93 mg, 31%).