Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:4]([NH:10][C:11]2[CH2:15][S:14][C:13](=[O:16])[N:12]=2)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[CH2:3][CH2:2]1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:15]2/[C:11]([NH:10][C@@H:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])=[N:12][C:13](=[O:16])[S:14]/2)[CH2:24][CH2:23]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)[C@@H](NC1=NC(=O)SC1)C1CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C1CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a solution of (2S)-2-cyclopropyl-N,N-dimethyl-2-[(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)amino]ethanamide (796 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1018 mg) in 2-propanol (10 mL) was added piperidinium acetate (479 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1111 mg).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[F:16][C:17]1[CH:18]=[C:19]2[C:29](=[CH:30][CH:31]=1)[C:22]([CH2:23][CH:24]([C:26]([OH:28])=[O:27])[NH2:25])=[CH:21][NH:20]2>>[C:26]([CH:24]([NH:25][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:23][C:22]1[C:29]2[C:19](=[CH:18][C:17]([F:16])=[CH:31][CH:30]=2)[NH:20][CH:21]=1)([OH:28])=[O:27]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(Cc1c[nH]c2cc(F)ccc12)C(=O)O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1c[nH]c2cc(F)ccc12)C(=O)O
Yield: 42 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 6-fluoro-DL-tryptophan to provide the title compound in 42% yield as yellow needles (recrystallization from MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:8]2[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]2)[CH:7]=1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:12]1[CH2:13][CH:8]([C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[CH2:9][C:10](=[O:15])[CH:11]=1
Reactant: [NH4+]
Reactant: Cc1ccc(Cl)cc1C1CC(=O)CC(=O)C1
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(Cl)cc1C1CC(=O)C=C(N)C1

Procedure:
A solution of 5-(5-chloro-2-methylphenyl)cyclohexane-1,3-dione (2.9 g) and ammonium acetate (2.8 g) in ethanol (50 ml) was refluxed for 14 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate, and the mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 1-amino-5-(5-chloro-2-methylphenyl)cyclohexen-3-one, which was dissolved in a mixture of ethanol (70 ml) and toluene (120 ml). To the mixture were added 3-oxobutylaldehydedimethylacetal (4.1 g) and powdery potassium hydroxide (0. 57 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (0.14 g) 30 minutes later; powdery potassium hydroxide (0.14 g) and 3-oxobutylaldehydedimethylacetal (0.33 g) 1 hour later; and powdery potassium hydroxide (0.14 g) 1.5 hours later, and then the mixture was stirred at the same temperature for 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure ethyl acetate was evaporated, and the residue was subjected to silica gel column (ethyl acetate-hexane) to give crystals, which were recrystallized from diisopropylether to give 7-(5-chloro-2-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.1 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:9]([CH3:12])(=[O:11])=[O:10])[CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:12][S:9]([C:6]1([CH2:4][OH:3])[CH2:8][CH2:7]1)(=[O:11])=[O:10]
Reactant: CCOC(=O)C1(S(C)(=O)=O)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CS(=O)(=O)C1(CO)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
1-Methanesulfonyl-cyclopropanecarboxylic acid ethyl ester (1 g, 5.2 mmol) is dissolved in dry tetrahydrofuran (20 mL) and cooled to 0° C. Lithium aluminium hydride (237 mg, 6.24 mmol) is added, the mixture allowed to warm to room temperature and stirred overnight. The mixture is cooled to 0° C. and saturated aqueous sodium sulfate solution is added with stirring. The precipitated solids are removed by filtration and the filtrate is partitioned between ethyl acetate and water. The organic phase is dried and the solvent removed under vacuum. The residue is purified by flash chromatography (ethyl acetate) to give the title compound (Yield 317 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1Cl.[F-:12].[K+].[F-].[Cs+].C1S(=O)(=O)CCC1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:12]
Reactant: [F-]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: [Cs+]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1
Yield: 93 %

Procedure:
1,500 parts of 3,4-dichloronitrobenzene, 680 parts of potassium fluoride and 5 parts of cesium fluoride are stirred in 1,500 parts of tetramethylenesulfone under nitrogen for 3 hours at 220° C. Working up takes place as described in Example 1(a). 1,275 parts (93% of theory) of 3-chloro-4-fluoronitrobenzene of melting point 41°-42° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[CH:27]=[CH:26][O:25][CH:24]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccoc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ncccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 1, part F, starting with 1.22 g (4.46 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperidine-1-carboxylic acid ethyl ester and 6.3 ml (6.24 mmol) of a freshly prepared 1 M solution of 3-bromomethylfuran in ethyl ether. The crude mixture was stirred at 60° C. for 3 hours. After standard work-up, 1 g (63% of yield) of the expected product was isolated.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:11][N:10]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:9]1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[CH3:2][C:1]1[S:42][C:6]([CH:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:11][N:10]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[N:5][N:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)s1

Procedure:
106 mg (0.231 mmol) of the compound from Example 121A and 187 mg (0.462 mmol) of Lawesson reagent were reacted according to the General Method 9. Yield: 10 mg (10% of theory)
Reaction SMILES: [CH2:1]([C:8]1S(=O)(=O)[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[C:22](#[N:27])/[CH:23]=[CH:24]/[C:25]#[N:26]>C(Cl)(Cl)Cl>[CH2:13]([C:10]1[CH:11]=[CH:12][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:24]([C:25]#[N:26])[C:23]=1[C:22]#[N:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: N#C/C=C/C#N
Reactant: CCCCCCCC1=CC=C(CCCCCCC)S1(=O)=O
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(CCCCCCC)c(C#N)c1C#N
Yield: 47.2 %

Procedure:
In a typical experiment 2,5-diheptylthiophene 1,1-dioxide (2 g, 6.4×10-3 mole) and fumaronitrile (0.5 g, 6.4×10-3 mole) in chloroform (5 ml) were heated in a sealed tube to 180° for 18 H. The contents of the tube were evaporated to dryness and chromatographed over silica (toluene as eluent) to afford 3,6-diheptylphthalonitrile (0.98 g, 47%) as a yellow solid. The material was recrystallised from ethanol to afford a colourless solid, mp 44°-46° C. 1H-nmr (CDCl3) shows S 7.52 (s, 2H); 2.85 (t, 4H); 1.0-1.9 (m, 20H); 0.90 (t, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OCC1C=CC=CC=1)=O)=[O:11]>CO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11]
Reactant: Cc1cccc(C)c1NC(=O)C1CCCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)C1CCCCN1
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Under nitrogen atmosphere in a Parr bottle, 8.2 mmoles of [Cbz-piperidine-2-carboxylic acid (2,6-dimethyl-phenyl)-amide] was dissolved in MeOH (100 mL). 10% Pd/C (0.5 g) was added, and the bottle was agitated under a hydrogen atmosphere (20 psi) for 30 minutes. The catalyst was filtered off using Millipore filter paper (washing with MeOH). The filtrate was concentrated to a thick syrup, yielding 1.75 grains (92% yield) of [piperidine-2-carboxylic acid (2,6-dimethyl-phenyl)-amide] as an off-white solid. The product was characterized by NMR (DMSO).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[N+:7]([C:10]1[CH:20]=[CH:19][C:13]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8]>C(OCC)(=O)C>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([CH:14]=[CH:15][C:16]([O:18][C:10]2[CH:20]=[CH:19][C:13]([CH3:14])=[CH:12][CH:11]=2)=[O:17])=[CH:19][CH:20]=1)([O-:9])=[O:8]
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1ccc(OC(=O)C=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phosphorus pentachloride (22 g) was added to 19.3 g of p-nitrocinnamic acid suspended in 300 ml of ethyl acetate, and the resulting suspension was stirred at room temperature for 1 hour. After the reaction, the solvent was removed by distillation under reduced pressure. The resulting precipitates of p-nitrocinnamoyl chloride were dissolved in 300 ml of ethyl acetate and 10.8 g of p-methylphenol was added to the resulting solution, after which 12 g of triethylamine was slowly added thereto at room temperature with constant stirring. After the mixture was subjected to reaction at room temperature for 1 hour, the reaction mixture was washed with 10% HCl, 10% NaOH and water in this order and dried on anhydrous magnesium sulfate. Then the solvent was removed by distillation under reduced pressure, whereby p-methylphenyl p-nitrocinnamate was obtained. Yield: 26.8 g (95%); melting point: 168°-170° C.; IR (cm-1): 1720, 1510, 1345. HCl).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[C:23]([NH:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([NH:14][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH:16]=1)(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cc(NC(=O)c2ccccc2)ccc1Cl
Reactant: O=C(O)c1ccc2ncccc2c1
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc3ncccc3c2)c1)c1ccccc1
Yield: 47 %

Procedure:
Using an analogous procedure to that described in Example 7, quinoline-6-carboxylic acid was reacted with N-(3-amino4chlorophenyl)benzamide to give the title compound in 47% yield; NMR Spectrum: (DMSOd6) 7.57 (m, 6H), 7.75 (m, 1H), 7.95 (d, 2H), 8.15 (d, 1H), 8.17 (d, 1H), 8.55 (d, 1H), 8.78 (s, 1H), 9.01 (m, 1H), 10.33 (s, 1H), 10.44 (s, 1H); Mass Spectrum: M−H− 400.
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:13])[C:5]2[CH:11]=[C:10]([Cl:12])[CH:9]=[N:8][C:6]=2[N:7]=1.[O:14]([CH2:21][CH2:22][CH2:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC([O-])(C)C.[K+]>CS(C)=O>[Cl:12][C:10]1[CH:9]=[N:8][C:6]2[N:7]=[C:2]([O:24][CH2:23][CH2:22][CH2:21][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:3][C:4](=[O:13])[C:5]=2[CH:11]=1
Reactant: O=c1[nH]c(Cl)nc2ncc(Cl)cc12
Reactant: OCCCOc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(OCCCOc2ccccc2)nc2ncc(Cl)cc12
Yield: 2.5 %

Procedure:
A solution of 2,6-dichloro-3H-pyrido[2,3-d]pyrimidin-4-one (60 mg, crude), 3-phenoxy-1-propanol [6180-61-6] (127 mg, 0.84 mmol), and KOtBu (62 mg, 0.55 mmol) in DMSO (1 ml) was heated in a microwave oven to 180° C. for 15 min. After filtration, the title compound (2.3 mg, 6.9 Amok; 2.5%, MS: m/e=330.3 [M−H−]) was obtained from the reaction mixture by preparative, reverse-phase HPLC (Agilent Zorbax XdB C18 column, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7 min, flow rate 30 ml/min).
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C([O-])([O-])=O.[K+].[K+].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>CC(C)=O>[CH3:16][S:17]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.1 %

Procedure:
To a suspension of 4-piperidone monohydrate hydrochloride (2.0 g, 13 mmol) and K2CO3 (9.0 g, 65.2 mmol) in acetone (40 ml) was added methanesulfonyl chloride (5.96 g, 52.1 mmol) at 0-5° C. The mixture was stirred at 25° C. for 24 h. The solid material was removed by filtration, and the filtrate was concentrated to dryness. The residue was purified by flash chromatography (silica gel, 80% ether in hexanes) to afford the desired ketone (1.20 g, 52%) as a colorless solid. mp 102-104° C.; 1H NMR (500 MHz, CDCl3) δ2.58 (t, J=6.4 Hz, 4H), 2.90 (s, 3H), 3.60 (t, J=6.4 Hz, 4H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11]C(C)([O-])C.[K+].IC>C1COCC1.O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH3:11])[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Ic1n[nH]c2ncccc12
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2cccnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a stirred solution of 3-iodo-1H-pyrazolo[3,4-b]pyridine (3.5 g, 14.3 mmol) in THF (70 mL) at 0° C. was added potassium tert-butoxide (1.92 g, 17.1 mmol) and the reaction mixture stirred at 0° C. for 1 h. Iodomethane (2.43 g, 1.07 mL, 17.1 mmol) was added drop-wise, then the mixture was warmed to rt. After 6 h the mixture was diluted with water, extracted with dichloromethane, then the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica, 20-60% ethyl acetate in hexanes) gave 3-iodo-1-methyl-1H-pyrazolo[3,4-b]pyridine (1.14 g, 4.4 mmol, 31%) as an off-white solid. MS (M+H)+=260.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[C:9]#[C:10][CH3:11])=[CH:4][CH:3]=1.Br[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.OCC1SC(B(O)O)=CC=1>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=2)=[CH:3][CH:4]=1)(=[O:12])[C:9]#[C:10][CH3:11]
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC#CC(=O)c1ccc(Br)cc1
Agent: OCc1ccc(B(O)O)s1
Product: CC#CC(=O)c1ccc(-c2ccc(C=O)cc2)cc1
Yield: 58 %

Procedure:
When the product of Step A and 4-carbaldehyde-boronic acid were substituted for 4-bromobenzaldehyde and 5-(hydroxymethyl)thiophen-2-ylboronic acid, respectively, in Example 22, Step A, the similar procedure afforded the title compound in 58% yield, as a creamy gum. 1H-NMR (CDCl3) 10.07 (s, 1H); 8.23 (d, 2H, J=8.4 Hz); 7.98 (d, 2H, J=8.4 Hz); 7.78 (d, 2H, J=8.24 Hz); 7.72 (d, 2H, J=8.54 Hz); 2.18 (s, 3H).
Reaction SMILES: [CH3:1][Si](Cl)(C)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1>CO>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17][CH3:1])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(CC(=O)O)c1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 17.25 h
Yield: 95.9 %

Procedure:
Trimethylsilyl chloride (182 g, 1.68 mol) was added dropwise to a solution of 3-methoxyphenylacetic acid (127 g, 0.77 mol) in methanol (1.0 L) over 1.1 hours. The reaction was stirred at room temperature for 17.25 hours, concentrated in vacuo, dissolved in ethyl acetate, dried over MgSO4, and concentrated in vacuo, to give a brown oil (133 g, 97%): 1H NMR (CDCl3/300 MHz) 7.24 (t, 1H, J=7.5 Hz), 6.83 (m, 3H), 3.80 (s, 3H), 3.69 (s, 3H), 3.60 (s, 2H).
Reaction SMILES: [OH:1][C:2]1([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]1([CH3:10])[CH3:9].Cl.[NH2:35][OH:36]>N1C=CC=CC=1>[OH:36]/[N:35]=[C:4]1/[C:3]([CH3:9])([CH3:10])[C:2]([C:11]2[S:12][C:13]([C:16]3[CH:21]=[C:20]([NH:22][C:23]4[N:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[CH:25][N:24]=4)[CH:19]=[C:18]([CH3:33])[CH:17]=3)=[CH:14][N:15]=2)([OH:1])[CH2:7][CH2:6][CH2:5]/1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCCC(=O)C3(C)C)s2)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCC/C(=N\O)C3(C)C)s2)c1
Temperature: 60 °C
Yield: 96.8 %

Procedure:
A mixture of the product of Step 2 (300 mg, 0.63 mmol) and hydroxylamine hydrochloride (87 mg, 1.26 mmol) in pyridine (3 mL) was heated to 60° C. for 1 h, concentrated, and purified by flash chromatography to afford the title compound (301 mg, 0.61 mmol). MS ESI: [M+H]+ m/z 492.2. 1H NMR (500 MHz, DMSO-d6) δ 10.36 (s, 1H), 10.26 (s, 1H), 8.84 (d, J=4.9, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.48 (s, 1H), 7.29 (d, J=4.9, 1H), 7.16 (s, 1H), 5.97 (s, 1H), 2.82 (m, 1H), 2.33 (s, 3H), 2.24:2.38 (m, 2H), 1.65-1.85 (m, 3H), 1.08 (s, 3H), 1.07 (s, 3H). rhSYK activity=+++
Reaction SMILES: I[Si](C)(C)C.C[O:7][CH2:8][CH2:9][N:10]1[C:14]([CH2:15][CH2:16][C:17]2[N:27]=[C:20]3[C:21]([CH3:26])=[N:22][CH:23]=[C:24]([CH3:25])[N:19]3[N:18]=2)=[N:13][C:12]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:11]1.CO.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:25][C:24]1[N:19]2[N:18]=[C:17]([CH2:16][CH2:15][C:14]3[N:10]([CH2:9][CH2:8][OH:7])[N:11]=[C:12]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:13]=3)[N:27]=[C:20]2[C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: COCCn1nc(-c2ccccc2)nc1CCc1nc2c(C)ncc(C)n2n1
Agent: C[Si](C)(C)I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ncc(C)n2nc(CCc3nc(-c4ccccc4)nn3CCO)nc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Iodotrimethylsilane (92.0 uL, 0.646 mmol) was added to a stirred solution of 2-{2-[2-(2-Methoxy-ethyl)-5-phenyl-2H-1,2,4-triazol-3-yl]ethyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (61 mg, 0.16 mmol) in Chloroform (5 mL) under an atmosphere of Argon at rt. The solution was stirred at rt 4 h. More Iodotrimethylsilane (184 uL, 1.29 mmol) was added and the mixture was stirred at rt ON. MeOH (10 ml) and solid sodium sulfite (0.5 g) was added and the mixture was stirred 30 min, filtered and evaporated. The crude product was purified by silica gel chromatography (Eluent: 0-5% MeOH in EtOAc). Yield: 27 mg (46%) of the title compound as a solid. LC-MS: m/z=364.5 (MH+), tR=1.30 min, Method C.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1.BrCC1C=CC([F:44])=CC=1Cl.C(OC(=O)C(C)(C)CSC1SC(N)=NC=1)C>>[Cl:1][C:2]1[CH:35]=[C:34]([F:44])[CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16][CH2:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:14][N:15]=1
Reactant: Fc1ccc(CBr)c(Cl)c1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Agent: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Product: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccc(F)cc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 1-bromomethyl-2-chloro-4-fluoro-benzene and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[C:14]([OH:22])[CH:13]=1)[CH3:2].[CH2:24](I)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][OH:21])=[C:14]([O:22][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)c1ccccc1Oc1ccc(CCCO)c(O)c1
Reactant: CCCCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1cc(Oc2ccccc2C(=O)OCC)ccc1CCCO
Temperature: 25 °C

Procedure:
A mixture of 600 mg of 2-[3-hydroxy-4-(3-hydroxypropyl)phenoxy]benzoic acid ethyl ester, 0.4 ml of decyl iodide, and 0.26 g of potassium carbonate in 50 ml of methyl ethyl ketone was stirred at reflux overnight. After cooling to room temperature, the mixture was filtered and the filtrate concentrated in vacuo. Purification of the residue by column chromatography over silica gel eluting with 20% ethyl acetate in hexane provided 510 mg of the desired subtitled intermediate as an oil, MS, IR, NMR.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)COCCO>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(c1ccccc1)c1ccc(C(=O)c2ccccc2)cc1
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: c1ccc(Cc2ccc(Cc3ccccc3)cc2)cc1
Temperature: 100 °C
Yield: 97.4 %

Procedure:
In a 4 neck, 1 liter flask fitted with thermocouple, mechanical stirrer, Barrett trap with condenser, nitrogen line, and stopper, was added 1,4-dibenzoylbenzene (90.5 g), hydrazine monohydrate (172.4 g) and diethyleneglycol (400 ml). The reaction mixture was heated at 100° C. for 1.5 hours. The mixture was then heated to 150° C. while collecting water and excess hydrazine hydrate in the Barrett trap. Potassium hydroxide (54.1 g) was slowly added over 0.5 hour while the temperature was slowly increased to 200° C. The temperature was maintained at 200° C. for 1 hour. The reaction was cooled to 80° C. and then poured into 500 ml water. The reactor was rinsed with an additional 550 ml water and combined with the quench solution. The water was extracted 3 times with 250 ml dichloromethane, the combined organic phases were washed with 500 ml water, dried over magnesium sulfate, filtered and the solvent removed on a rotary evaporator to give 1,4-dibenzylbenzene as a white solid (79.5 g, 97.4% yield).