Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([C:26]2[O:30][N:29]=[CH:28][C:27]=2[CH2:31][CH2:32][C:33](O)=[O:34])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([C:33](=[O:34])[CH2:32][CH2:31][C:27]3[CH:28]=[N:29][O:30][C:26]=3[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCc1cnoc1-c1ccccc1)N1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A mixture of N-diphenylmethylpiperazine (0.85 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.70 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.55 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.69 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-diphenylmethyl-N′-[3-(5-phenyl-4-isoxazolyl)propionyl]piperazine (1.35 g, yield 93%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). NMR (CDCl3) δ: 2.26–2.42 (4H, m), 2.50–2.64 (2H, m), 2.94–3.08 (2H, m), 3.32–3.44 (2H, m), 3.56–3.68 (2H, m), 4.22 (1H, s), 7.12–7.54 (13H, m), 7.66–7.86 (2H, m), 8.21 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C1(C)C=CC=CC=1>[CH2:12]([NH:20][C:21](=[O:22])[O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: CCCCCCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCCCCCNC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
100 mL toluene, 10 g 2-nitrobenzyl alcohol and 11.4 mL octyl isocyanate were introduced into a 200-mL roundbottom flask and heated under reflux for 2 hours under a nitrogen blanket. After cooling, the reaction solution was washed several times with water, and the toluene solution thereby afforded was then dried over sodium sulfate. The sodium sulfate was thereafter filtered off and the solvent was eliminated from the filtrate using a rotary evaporator. The resulting solid was recrystallized twice from hexane to yield 12.5 g ortho-nitrobenzyl n-octylcarbamate as light-yellow, needle-like crystals. mp=70°-71° C. Infrared absorption=3331 cm-1, 1691 cm-1.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=1.[CH3:16][O:17][C:18](=[O:22])[CH2:19][C:20]#[N:21].C[O-].[Na+]>CO>[CH3:16][O:17][C:18]([C:19]1[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]([F:14])([F:13])[F:12])[CH:5]=2)=[N:2][O:1][C:20]=1[NH2:21])=[O:22]
Reactant: ON=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: COC(=O)CC#N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(-c2cccc(OC(F)(F)F)c2)noc1N
Yield: 83.5 %

Procedure:
In a similar manner as described in Preparation Example 17, by using methanol (160 mL), N-hydroxy-3-(trifluoromethoxy)benzimidoylchloride (8.00 g, 33.39 mmol), methylcyanoacetate (4.31 g, 43.41 mmol) and sodium methoxide (3.61 g, 66.78 mmol), a white solid required compound (8.42 g, 27.87 mmol, 83%) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:14][C:12]1[CH2:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])[CH2:9][C:10](=[O:15])[CH:11]=1)[CH3:18]
Reactant: O=C1CC(=O)CC(c2ccccc2O)C1
Reactant: CCO
Solvent: O
Product: CCOC1=CC(=O)CC(c2ccccc2O)C1

Procedure:
5-(2-Hydroxyphenyl)-1,3-cyclohexanedione (5.0 g) was dissolved in ethanol (225 ml). The solution was heated under reflux for 3h and diluted to 2 l. by the addition of water. The solid which separated out was collected by filtration, washed with water and dried. Recrystallisation from ethanol afforded the title compound (1.5 g) as pale yellow prisms m.p. 194°-197°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([C:18]([F:19])([F:20])[F:21])=[N:13]3)=[CH:4][C:3]=1[O:22][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1OCc1cccnc1

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (prepared as described in Example 35 part a), 50.0 mg, 0.16 mmol), caesium carbonate (159 mg, 0.49 mmol) and 3-(chloromethyl)pyridine hydrochloride (31.9 mg, 0.20 mmol) were stirred together in DMF (3 mL) at room temperature under nitrogen overnight. The mixture was partitioned between dichloromethane (3 mL) and water (3 mL), then was filtered through a PTFE cartridge. The separated organic phase was concentrated in vacuo, and residue was purified by flash chromatography on silica gel, eluting with 1:1 dichloromethane:ethyl acetate, then with ethyl acetate, affording 5-[4-fluoro-3-(pyridin-3-ylmethoxy)phenyl]-2-trifluoromethyl[1,8]naphthyridine as a colourless oil, which solidified upon trituration with isohexane (45.1 mg, 70%). δH (400 MHz, CDCl3) 5.22 (2H, s), 7.06-7.12 (2H, m), 7.30-7.38 (2H, m), 7.52 (1H, d, J 4.3), 7.79 (1H, d, J 8.6), 7.81-7.83 (1H, m), 8.39 (1H, d, J 8.6), 8.64 (1H, dd, J 1.6 and 4.7), 8.69 (1H, d, J 2.0), 9.26 (1H, d, J 4.3). m/z (ES+) 400 [MH]+.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH3:14][CH2:15][Mg+].[Br-].Cl>C(OCC)C>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]([OH:13])[CH2:14][CH3:15])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC[Mg+]
Reactant: CC(C)CC1=CCC(C=O)C(C)C1
Agent: Cl
Agent: [Br-]
Solvent: CCOCC
Product: CCC(O)C1CC=C(CC(C)C)CC1C
Temperature: 2.5 °C
Yield: 101.9 %

Procedure:
4-isobutyl-6-methylcyclohex-3-enecarbaldehyde 3b (0.5 g, 2.8 mmol) was dissolved in diethyl ether (10 ml). The solution was cooled to 0-5° C. under nitrogen and EtMgBr (3M, 1.4 ml, 4.2 mmol) added over 10 min with stirring. The temperature was allowed to rise to room temperature and the reaction stirred for 10 min. The reaction mixture was poured slowly onto a vigorously stirred mixture of 2M HCl and ice. After stirring for 15 min the phases were separated and the lower aqueous layer extracted twice with MTBE. The organic phases were combined and washed with sat. NaHCO3 solution and brine to give a neutral pH. After drying (MgSO4) the organic phase was concentrated in vacuo to give 0.6 g of oil. The oil was purified by flash chromatography (MTBE/hex.1:4) to give 4e as a 2:85:8:4 mixture of diastereomers (0.54 g, 91% yield, colorless oil, >99% pure). Subsequent distillation provided an olfactory pure sample (0.4 g).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[CH3:42][N:43]([CH3:50])[CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:47]1[CH2:48][CH2:49][CH:44]([N:43]([CH3:50])[CH3:42])[CH2:45][CH2:46]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CN(C)C1CCNCC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N(C)C)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-dimethylamino-piperidine dihydrochloride (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:34]([N:37]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[N:38]1)([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:39]3[CH:40]=[CH:41][N:37]([CH:34]([CH3:36])[CH3:35])[N:38]=3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(-c3ccn(C(C)C)n3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 22b using [3-(4-bromobenzyl)-8-chloro-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid tert-butyl ester and 1-isopropyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([NH2:11])=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1)[CH3:2].[N:12]#[C:13]Br.[NH4+].[OH-]>CO.O>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=2[N:11]=[C:13]1[NH2:12])[CH3:2]
Reactant: N#CBr
Reactant: CCNc1ccc(F)cc1N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCn1c(N)nc2cc(F)ccc21
Temperature: 25 °C

Procedure:
To a solution of N1-ethyl-4-fluoro-benzene-1,2-diamine (1.54 g, 10.0 mmol) in MeOH (20 mL) and H2O (20 mL) was added cyanogen bromide (2.1 mL, 10.5 mmol, 5.0 M in acetonitrile). The resulting mixture was stirred at room temperature over night. The resulting mixture was then adjusted to pH>9 with concd NH4OH and the resulting solid was collected by filtration, washed with H2O and hexanes to yield 1-ethyl-5-fluoro-1H-benzimidazol-2-ylamine MS 180 (M+1)+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[O:10][N:9]=[CH:8][C:7]=1[C:11](Cl)=[O:12].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:11]([C:7]2[CH:8]=[N:9][O:10][C:6]=2[CH3:5])=[O:12])=[CH:18][CH:17]=1
Reactant: Cc1oncc1C(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)c2cnoc2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of aluminium chloride (10 g) and 5-methylisoxazole-4-carbonyl chloride (2.7 g) in methoxybenzene (50 ml) was stirred at room temperature for 16 hours. The mixture was quenched with excess ice and extracted with ether (3×200 ml). The combined organic layers were washed with water (3×500 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was purified by chromatography on silica eluted with a mixture of ethyl acetate and cyclohexane (1:10) followed by HPLC on silica eluted with a mixture of ethyl acetate and hexane (1:20) to give 4-(4-methoxybenzoyl)-5-methylisoxazole (compound 18, 0.35 g) as a white solid mp 78°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([OH:10])[C:7]([CH2:11]/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([OH:20])[CH:5]=1.CO>Cl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([OH:10])[C:7]2[CH2:11][CH:12]([CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:20][C:6]=2[CH:5]=1)=[O:21]
Reactant: COC(=O)c1cc(O)c(C/C=C/c2ccccc2)c(O)c1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(O)c2c(c1)OC(Cc1ccccc1)C2
Yield: 76.9 %

Procedure:
A solution of 3,5-dihydroxy-4-((E)-3-phenyl-allyl)-benzoic acid methyl ester (220 h) (12 g, 0.032 mol) in HCl (g)/MeOH (4 N, 150 mL) was stirred at room temperature for 2 days. The reaction solution was concentrated to give a brown solid. The crude solid was re-crystallized from EtOAc to give the product (7 g) as a yellow solid. The mother liquid was concentrated to give a brown solid (5 g). The total yield is 98%. 1H NMR (400 MHz, CDCl3): δ 9.90 (br, 1H), 7.27˜7.46 (m, 5H), 7.00 (s, 1H), 6.87 (s, 1H), 5.07 (d, 1H), 3.78 (s, 3H), 2.65 (d, 2H), 2.16 (m, 1H), 1.92 (m, 1H).
Reaction SMILES: [CH2:1]([S:3]([CH:6]=[CH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])(=[O:5])=[O:4])[CH3:2]>Cl.CN(C)C=O.O.[Pd]>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:17][C@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[CH3:23])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Agent: [Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCS(=O)(=O)CCc1ccc2[nH]cc(C[C@H]3CCCN3C)c2c1
Yield: 69.6 %

Procedure:
(R)-5-(2-Ethylsulphonylethenyl)-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole (157 mg) was dissolved in a mixture of ethanolic hydrogen chloride [prepared by addition of acetyl chloride (0.043 mL) to ethanol (10 mL)], N,N-dimethylformamide (7.5 mL) and water (0.1 mL) and the solution was shaken under a hydrogen atmosphere (15 psi) at room temperature for 18 hours in the presence of 10% palladium on carbon (150 mg). The mixture was filtered through Arbacel (trade mark) filter aid and the residue was washed well with ethanol. The combined filtrate and washings were evaporated under reduced pressure and the residual oil was partitioned between ethyl acetate and 2M aqueous sodium carbonate solution. The organic layer was separated, washed three times with water followed by brine and then dried (Na2SO4). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/methanol/concentrated aqueous ammonia (90:10:1) gave the title compound as a gum (110 mg): TLC (CH2Cl2 /C2H5OH/NH3 ; 90:10:1): Rf=0.3; [α]25D =+62° (methanol, c=0.10). Anal. Calcd for C18H26N2O2S. 0.05 CH2Cl2 : C,63.21; H,7.67; N,8.17. Found: C,63.55; H,7.61; N,8.41.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:27])([F:26])[F:25])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:28]([OH:33])([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:6][CH:5]=1.[CH3:34]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[C:24]([F:25])([F:27])[F:26])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:28]([CH2:31][CH3:32])([O:33][CH3:34])[CH2:29][CH3:30])=[CH:6][CH:5]=1
Reactant: CCC(O)(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(CC)(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1C(F)(F)F
Reaction time: 0.08 h
Yield: 68.1 %

Procedure:
Sodium hydride (60% in oil, 25.4 mg, 0.635 mmol) was added to a stirred solution of 3-{9-chloro-1-[4-chloro-2-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl}pentan-3-ol (250 mg, 0.529 mmol) in N,N-dimethylformamide (5.0 mL) at room temperature. After stirring 5 min, methyl iodide (113 mg, 0.794 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (175 mg, 0.360 mmol, 68%).
Reaction SMILES: C[Si](C)(C)[C:3]1[CH:10]=[CH:9][C:6](C=O)=[C:5]([C:11]#[CH:12])[CH:4]=1.[C:15](=[O:18])([O-])[O-].[Na+].[Na+]>CO>[C:11]([C:5]1[CH:6]=[CH:9][C:10]([CH:15]=[O:18])=[CH:3][CH:4]=1)#[CH:12]
Reactant: O=C([O-])[O-]
Reactant: C#Cc1cc([Si](C)(C)C)ccc1C=O
Agent: [Na+]
Solvent: CO
Product: C#Cc1ccc(C=O)cc1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
The trimethylsilyl groups were subsequently subjected to a deprotecting reaction in accordance with reaction (2) in FIG. 2. Specifically, 4.0 g of 4-trimethylsilyl ethynyl benzaldehyde was dissolved in 20 mL of methanol, the solution was stirred for 30 minutes under nitrogen gas, 0.19 g of sodium carbonate was added, and the product was stirred for another 3 hours at room temperature. The solvent was removed at a reduced pressure, the residue was washed with a 5% aqueous solution of sodium bicarbonate and extracted with dichloromethane, anhydrous sodium sulfate was added, and the product was dried. The dried product was filtered off and the solvent was removed at a reduced pressure. The product was dried in a vacuum, yielding the target compound 4-ethynyl benzaldehyde with an aldehyde odor as white crystals with the yield of 99%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14](O)=[O:15])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([CH2:14][OH:15])[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1-c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1-c1ccccc1
Temperature: 0 °C
Yield: 64.5 %

Procedure:
4-bromobiphenyl-2-carboxylic acid (5.71 g, 20.61 mmol) was dissolved in THF (50 mL) and cooled to 0° C. 1.0M borane tetrahydrofuran complex (41.2 mL, 41.2 mmol) was added dropwise over 15 min. and allowed to warm up to r.t. overnight. The reaction was diluted with EtOAc and washed with water, sat. ammonium chloride, and then brine. The organic layer was collected, dried over MgSO4, filtered and evaporated to give the crude product. The crude product was purified by flash chromatography on the Biotage (5-35% EtOAc:Hex) to give (4-bromobiphenyl-2-yl)methanol (3.5 g, 13.30 mmol, 65% yield) as a light orange oil. LCMS: rt=1.43 min.; Phenomenex-Luna C-18 (5μ) (3.0×50 mm); Solvent A=10% acetonitrile—90% water—0.1% TFA, Solvent B=90% acetonitrile—10% water—0.1% TFA; gradient 0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 mL/min; inj. vol.=5 uL; wavelength=220. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.60 (d, J=5.77 Hz, 2H) 7.15 (d, J=8.28 Hz, 1H) 7.29-7.35 (m, 2H) 7.36-7.46 (m, 3H) 7.48 (dd, J=8.28, 2.01 Hz, 1H) 7.75 (d, J=2.01 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH2:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=[CH2:12]
Reactant: C=CCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCCCCCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
p-hydroxybenzoic acid (33.2 g), 8-bromo-1-octene (57.3 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate and then filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and washed with water. This was dried to give TP-5C (63.3 g, 85%).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[F:21][C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28]>>[F:21][C:22]1[S:26][C:25]([NH:27][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])=[N:24][C:23]=1[CH3:28]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: Cc1nc(N)sc1F
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nc(C)c(F)s2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 5-Fluoro-4-methyl-thiazol-2-ylamine instead of 3-Chloroaniline acid to yield the final compound as an orange solid, MS (ISP): m/e=364.2 (M+H)+.
Reaction SMILES: C1C(=O)N([O:8][C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.CCN(CC)CC.[CH3:26][CH2:27][O:28][C:29]([CH3:31])=O>CC#N>[O:28]1[CH2:29][CH2:31][C@H:26]([O:8][C:9](=[O:10])[O:11][N:12]2[C:13](=[O:14])[CH2:15][CH2:16][C:17]2=[O:18])[CH2:27]1
Reactant: CCOC(C)=O
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Yield: 92 %

Procedure:
Compound 21 (250 mg, 2.84 mmol), N,N′-disuccinimidyl carbonate (799 mg, 3.12 mmol), and Et3N (431 mg, 4.27 mmol) in CH3CN (5 mL) were stirred for 12 hours at room temperature. Then the reaction mixture was diluted with EtOAc (20 mL), washed with brine, then concentrated under reduced pressure to obtain compound 22 (595 mg, 92%) as a solid. M.P.: 97-99° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=3)[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccc(Sc3ccc(C#N)cn3)c2)ccc(C(C)=O)c1O
Yield: 139.2 %

Procedure:
Using the method of Preparation 166 using 6-(3-(hydroxymethyl)phenylthio) nicotinonitrile (1.25 g, 5.15 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.00 g, 5.15 mmol) affords the title compound (3.00 g). MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[CH2:20]([N:23]=[C:24]=[O:25])[CH2:21][CH3:22]>>[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:24]([NH:23][CH2:20][CH2:21][CH3:22])=[O:25])#[N:3]
Reactant: CCCN=C=O
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CCCNC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 176b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride (Example 176c) and propyl isocyanate in 100% yield as a light yellow solid. MS 333 (MH+).