Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]([CH3:23])([CH3:22])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([C:18]([O:20]C)=[O:19])=[N:16][CH:17]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.C1COCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([CH3:23])([CH3:22])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cnc(OCC(C)(C)OCc2ccc(OC)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(COC(C)(C)COc2cnc(C(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of methyl 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazine-2-carboxylate (3.5 g), 1 M aqueous sodium hydroxide solution (35 mL), methanol (35 mL), and THF (35 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by washing with ethyl acetate. To the aqueous layer was added 1 M hydrochloric acid to adjust the pH to 4, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazine-2-carboxylic acid (2.5 g) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([O:32]CC)=[O:31])=[CH:4][CH:3]=1.[NH:39]1[CH2:42][CH2:41][CH2:40]1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:39]1([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:11]4[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]5[CH:27]=[CH:26][C:25]6[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=6)[N:19]=5)=[CH:15][C:10]=4[N:9]=[C:8]3[CH2:28][C:29]([CH3:36])([CH3:35])[C:30]([OH:32])=[O:31])=[CH:37][CH:38]=2)[CH2:42][CH2:41][CH2:40]1
Reactant: C1CNC1
Reactant: CCOC(=O)C(C)(C)Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Product: CC(C)(Cc1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(N2CCC2)cc1)C(=O)O
Temperature: 95 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a 5 mL microwave vial were added a stirbar, ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylpropanoate (100 mg, 0.2 mmol), azetidine (20 mg, 0.4 mmol), JohnPhos (32 mg, 0.12 mmol), t-BuOK (35 mg, 0.4 mmol), and Pd2(dba)3 (60 mg, 0.07 mmol). The vial was capped and flushed with N2 before adding 3 mL of N2 sparged toluene. The resulting mixture was heated at 95° C. for 18 hours. The vial was cooled to RT and concentrated to dryness. The resulting residue was dissolved in MeOH (9 mL) and THF (9 mL). To the solution was added 5% aqueous NaOH (2 mL) and the mixture was stirred at 40° C. overnight. The mixture was cooled to RT and acidified to ˜pH=4-5 with 6 N HCl, then extracted with EtOAc (3×20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated to dryness and purified by prep-HPLC to give the title compound (50 mg, 30%). MS (ESI): mass calcd. for C32H32N4O3, 520.25; m/z found, 521.2 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.35 (d, J=8.9, 1H), 8.05 (d, J=8.6, 1H), 7.93 (d, J=7.8, 1H), 7.82-7.69 (m, 2H), 7.60 (t, J=7.6, 1H), 7.33-7.20 (m, 3H), 7.08-6.97 (m, 2H), 6.92 (d, J=8.3, 1H), 6.38 (d, J=8.3, 1H), 5.50-5.36 (m, 4H), 3.79 (t, J=7.2, 2H), 3.35-3.32 (m, 2H), 3.14 (s, 2H), 2.40-2.25 (m, 2H), 1.28 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]3C=CC=C[CH:30]=3)=[O:26])[CH2:21][CH2:20]2)=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:7]=1.[CH3:35]CO>[Pd]>[CH3:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]3([CH3:35])[CH2:30][CH2:29]3)=[O:26])[CH2:21][CH2:20]2)=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[N:11][N:10]=[N:9]2)[CH:7]=1
Reactant: CCO
Reactant: Cc1cc(-n2cnnn2)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Product: Cc1cc(-n2cnnn2)cnc1OCC[C@@H]1C[C@@H]1C1CCN(C(=O)OC2(C)CC2)CC1

Procedure:
A solution of benzyl 4-[(1R,2S)-2-(2-{[3-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl]oxy}ethyl)cyclopropyl]piperidine-1-carboxylate (920 mg, 1.99 mmol) in 5 ml of EtOH was treated with 200 mg of Pd/C under a balloon of H2 gas for 3.5 hours. The suspension was filtered through a plug of celite and the filtrate was concentrated to afford the title compound as a crude product to be used for the next step. LC/MS (m/z): 329 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:9]#[N:10])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC(c1ccc(F)cc1)c1ccc(Cl)cn1
Yield: 96.8 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (9.13 g), 2-chloro-5-chloropyridine (10.0 g.) and sodium 4-methylphenylsulfinate (24.1 g) in THF (280 ml) was added sodium hydride (5.41 g, 60%) at 0° C., and the mixture was heated to reflux for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 5-chloro-2-(α-cyano-4-fluorobenzyl)pyridine (16.14 g) as yellow oil.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:8][C:7]([C:9](=[O:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+].O>C(O)(=O)C>[Br:1][C:5]1[CH:6]=[C:7]([C:9](=[O:13])[C:10]([OH:12])=[O:11])[S:8][C:4]=1[CH3:3]
Reactant: BrBr
Reactant: Cc1ccc(C(=O)C(=O)O)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(C(=O)C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 91.4 %

Procedure:
Br2 (0.665 mL, 12.9 mmol) was added dropwise to a solution of (5-methylthiophen-2-yl)-oxo-acetic acid (1.05 g, 6.15 mmol) and sodium acetate (757 mg, 9.23 mmol) in 10 ml of glacial acetic acid and stirred at room temperature for 6.5 hours. The reaction mixture was poured into 150 ml water and extracted with diethyl ether (2×75 ml). The combined diethyl ether layers were extracted with aqueous Na2S2O3, the organic layer was then dried over sodium sulfate, and concentrated under vacuum to provide crude (4-bromo-5-methylthiophen-2-yl)-oxo-acetic acid (1.40 g, 91%). 1H NMR (300 MHz, CDCl3) δ8.35 (1H, s), 2.54 (3H, s).
Reaction SMILES: C([NH:8][C@@H:9]([CH2:13][O:14][CH2:15][CH3:16])[C:10]([OH:12])=O)(OC(C)(C)C)=O.C(N1CCOCC1)C.[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C([O-])(O)=O.[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C.ClCCl>[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:10](=[O:12])[C@@H:9]([NH2:8])[CH2:13][O:14][CH2:15][CH3:16])[CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOC(=O)N1CCNCC1
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)COCC)CC1
Reaction time: 12 h

Procedure:
To a solution of 146 mg (S)-N-Boc-2-amino-3-ethoxypropionic acid in 2 ml DMF were added 0.34 ml N-ethylmorpholine, 200 mg 1-butoxycarbonylpiperazine hydrotrifluoroacetate and 219 mg TOTU. After stirring for 12 h it was added saturated aqueous NaHCO3 and the mixture was loaded on a Chem Elut® cartridge, the crude product being eluted with ethyl acetate. The solution was concentrated, the residue obtained dissolved in 5 ml dichloromethane and stirred in the presence of 1 ml TFA. After 12 h stirring it was concentrated and the residue codistilled twice with toluene.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C>[C:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][C:13](=[O:23])[C:14]3[CH:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(NC1CCN(c2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Solvent: CCO
Product: Nc1ccc(C(=O)NC2CCN(c3ccccc3)C2)cc1

Procedure:
A suspension of 10 g. of 1-phenyl-3-(4-nitrobenzamido)pyrrolidine in 250 ml. of 95% ethanol containing 5% palladium on charcoal was shaken in a Paar hydrogenator in three atmospheres of hydrogen at room temperature. The reduction mixture was filtered and the filtrate concentrated to give 3.8 g. of crystalline product which melted at 213-216° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[S:33]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
In a mixed solvent of 15 ml pyridine and 120 ml of methylene chloride was dissolved methyl 22-hydroxydocosanoate (1.70 g, 4.59 mmoles). p-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was gradually added to the obtained solution under ice-cooled condition, over a period of 1 hour, and the mixture was stirred for 14 hours in a refrigerator. Then, p-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was added to the reaction mixture, and reaction was effected for 24 hours. After the completion of reaction, the reaction mixture was treated in the same manner as in Reference Example 1, to give methyl 22-tosyloxydocosanoate (2.28 g, 75%) having the following properties.
Reaction SMILES: [CH:1]1([C:6]([NH:8][CH:9]([CH2:15][SH:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1>C1(C)C=CC=CC=1>[CH:1]1([C:6]2[S:16][CH2:15][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(CS)NC(=O)C1CCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CSC(C2CCCC2)=N1

Procedure:
Tosic acid monohydrate (0.78 g) was added to a solution of ethyl 2-(cyclopentanecarboxamido)-3-mercaptopropanoate [Carboxylic Acid 2, step a] (5 g) in toluene (40 mL). The resulting mixture was heated at reflux under Dean and Stark conditions for 6 h. The reaction was allowed to cool, then the toluene solution was washed with saturated sodium bicarbonate solution (20 mL) and the solvent evaporated. The residue was azeotroped with toluene. The resulting white solid was purified by silica gel chromatography eluting with 9:1 isohexane:ethyl acetate. The fractions containing the product were combined and evaporated to give the subtitled compound as a clear oil. Yield 3.2 g.
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([O:19][CH2:20][CH:21]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:22]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:23]1[C:22]2[CH:21]([CH2:20][O:19][C:17](=[O:18])[CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:34])=[O:5])[S:12][CH:13]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)OCC2c3ccccc3-c3ccccc32)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CC(=O)OCC2c3ccccc3-c3ccccc32)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
To a solution of 2-({4-[2-(9H-fluorene-9-ylmethoxy)-2-oxoethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (260 g) obtained in Example 461-1 in dichloromethane (400 mL) was added trifluoroacetic acid (100 mL), and the mixture was stirred at room temperature overnight and heated at 45° C. with stirring for 8 hr. The reaction mixture was concentrated, ethyl acetate was added, and the organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (250 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH2:18])=[O:5])[CH3:2].[C:19](OCC)(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)csc1N
Product: CCOC(=O)CC(=O)Nc1scc(-c2ccc(Cl)cc2)c1C(=O)OCC

Procedure:
A solution of 2-Amino-4-(4-chloro-phenyl)-thiophene-3-carboxylic acid ethyl ester (4a) (1.759 g, 6.24 mmol) in diethyl malonate (8.0 g, 50 mmol) was heated at 180° C. for 4 hours. The excess diethyl malonate was removed under reduced pressure to give the title compound. MS (DCI/NH3) m/e 396 (M+H)+; 1H NMR (300 MHz, CDCl3): δ ppm 12.21 (s, 1H), 7.33–7.20 (m, 5H), 6.62 (s, 1H), 4.31 (q, J=7.12, 2H), 4.15 (q, J=7.12, 2H), 3.61 (s, 2H), 1.33 (t, J=7.12, 3H), 0.99 (t, J=7.12, 3H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.CN(C=O)C.[OH-].[K+]>O>[C:22]1([C:19]2[CH:18]=[CH:17][C:16]([NH:15][CH2:2][C:3]([NH:5][C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[C:8]([OH:10])=[O:9])=[O:4])=[CH:21][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1ccc(-c2ccccc2)cc1)Nc1ccccc1C(=O)O

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), para-aminobiphenyl (13.12 g, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. The resulting air-sensitive material was triturated with ethyl acetate (100 mL), filtered, and rinsed with ethyl acetate (2×25 mL) to yield, after drying, 8.18 g (76%) of the title compound as a tan solid; 1H NMR (DMSO-d6) δ 13.4 (broad s, 1H), 12.05 (s, 1H), 8.75 (d, J=8.4, 1H), 7.95 (dd, J=7.4, J=1.2, 1H), 7.60 (td, J=7.2, J=1.2, 1H), 7.54 (d, J=7.6, 2H), 7.45 (d, J=8.8, 2H), 7.37 (t, J=7.6, 2H), 7.22 (t, J=7.6, 1H), 7.13 (t, J=7.6, 1H), 6.69 (d, J=8.4, 2H), 6.7 (broad s, 1H), 3.90 (s, 2H); 13C NMR (DMSO-d6) a 170.74, 169.12, 147.71, 140.60, 140.36, 134.20, 131.14, 128.87, 128.74, 127.28, 125.96, 125.55, 122.69, 119.40, 115.97, 112.85, 48.87; MS (EI, m/z) 328 (M-H2O+).
Reaction SMILES: F[C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]([C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1)=[O:37].CN1CCCC1=O>O>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][C:2]2[C:3]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:40][CH:39]=1)=[O:37]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 150 °C

Procedure:
To a 350 mL pressure vial is added tert-butyl 4-(3-fluoropyrazin-2-yl)piperidine-1-carboxylate (200 mg, 0.711 mmol), Cs2CO3 (417 mg, 1.280 mmol), and (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (305 mg, 1.280 mmol) and N-methylpyrrolidinone (1.3 mL). The reaction was heated in the microwave at 150° C. 1 h. The reaction was added to a flask containing H2O (20 mL) with rapid stirring. The resulting slurry was filtered and the solid filter cake washed with H2O (3×5 mL). The solid was purified by ISCO (40 g SiO2, 0-20% MeOH/CH2Cl2) to give tert-butyl 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as a brown solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1.[C:22](=[O:25])([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:22]([C:2]1[CH:11]=[CH:10][CH:5]=[CH:4][C:3]=1[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:21])=[CH:7][C:8]([O:12][C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[N:9]2)=[CH:4][CH:3]=1)=[O:25]
Reactant: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(Oc2ccc(C#N)cc2)nc2cc(-c3ccccc3C=O)ccc12

Procedure:
Prepared analogously to Example 27e from 4-[(7-bromo-4-methyl-quinolin-2-yl)oxy]-benzonitrile, 2-formylbenzeneboric acid, sodium carbonate and tetrakis-(triphenylphosphine)-palladium (0) in toluene/water.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.N1C=CN=C1.[C:16]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])([CH3:18])[CH3:17]>ClCCl.O>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:22])[CH3:21])=[C:4]([F:10])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(F)cc(Br)cc1F
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Bromo-2,6-difluorophenol D1c (5.0 g, 24 mmol) is dissolved in dichloromethane (50 mL) and treated with imidazole (2.28 g, 33.5 mmol). The colorless solution is treated in portions, with stirring, with tert-butylchlorodimethylsilane (4 g, 26 mmol). The mixture is stirred at room temperature overnight. The mixture is diluted with water (150 mL) and extracted with dichloromethane. The organic phase is washed with sat. NH4Cl solution, dried over Na2SO4 and concentrated in vacuo. Purification of the crude material by flash chromatography (hexanes/ethyl acetate gradient) affords (4-bromo-2,6-difluorophenoxy)(tert-butyl)dimethylsilane D1d as a clear oil. 1H-NMR (400 MHz, CDCl3) δ=7.05 (d, J=7.2 Hz, 2H), 1.00 (s, 9H), 0.19 (s, 6H); no MS spectrum could be obtained.
Reaction SMILES: Cl.[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12]3)[C:6]=12.[C:17]1([N:23]2[CH:27]=[C:26]([C:28](O)=[O:29])[N:25]=[CH:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:2]1[N:3]=[CH:4][N:5]2[CH:10]=[CH:9][N:8]=[C:7]([N:11]3[CH2:15][CH2:14][C@H:13]([NH:16][C:28]([C:26]4[N:25]=[CH:24][N:23]([C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=5)[CH:27]=4)=[O:29])[CH2:12]3)[C:6]=12
Reactant: N[C@H]1CCN(c2nccn3cnnc23)C1
Reactant: O=C(O)c1cn(-c2ccccc2)cn1
Agent: CCN(CC)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1CCN(c2nccn3cnnc23)C1)c1cn(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a suspension of (S)-1-([1,2,4]triazolo[4,3-a]pyrazin-8-yl)pyrrolidin-3-amine hydrochloride salt (109 mg, 0.4 mmol) and 1-phenyl-1H-imidazole-4-carboxylic acid (76 mg, 04 mmol) in DMF (5 mL) was added diethylisopropyl amine (650 mg, 5 mmol), followed by HATU (160 mg, 0.41 mmol). The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solutions of KH2PO4 and NaHCO3, followed by brine. The organic layer was concentrated in vacuo and the residue purified by reverse phase HPLC (acetonitrile-H2O with 0.1% TFA as eluent) to give 100 mg of the title compound (67% yield) as a white solid. MS: (ES) m/z found 375.1.
Reaction SMILES: C([N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)=O)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:29][C:26]([F:27])([F:28])[S:23]([C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[C:10]3[CH2:9][NH:8][CH2:31][CH2:30][C:11]=3[N:12]=[CH:13][N:14]=2)=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: O=S(=O)(c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cc1)C(F)(F)F
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1ccc(Nc2ncnc3c2CNCC3)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
6-Benzyl-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[4,3-d]pyrimidin-4-amine (270 mg, 0.55 mmol) was dissolved in anhydrous chloroform (10 mL) and 1-chloroethylchloroformate was added (0.18 mL, 1.65 mmol). After stirring for 30 min, N,N-diisopropylethylamine was added (0.24 mL, 1.65 mmol) and the mixture was stirred for an additional 2 h. The chloroform was removed under vacuum and 30 ml of methanol was added and the mixture was heated for 30 min. Upon reaction completion, the methanol was removed and the residue was dissolved in ethyl acetate and washed with sat. NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give the product (163 mg, 83%).