Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:40]=[C:41]([S:46]([N:49]([CH3:51])[CH3:50])(=[O:48])=[O:47])[CH:42]=[CH:43][C:44]=1[F:45]>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:40]=[C:41]([S:46]([N:49]([CH3:50])[CH3:51])(=[O:47])=[O:48])[CH:42]=[CH:43][C:44]=1[F:45])([CH3:23])([CH3:22])[CH3:21]
Reactant: CN(C)S(=O)(=O)c1ccc(F)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CN(C)S(=O)(=O)c1ccc(F)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-4-fluoro-N,N-dimethylbenzenesulfonamide (Intermediate 138), the title compound was obtained as a colorless oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20](C)[C:21](=O)C)=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(OCC)(=O)C>CO.[OH-].[Na+]>[CH3:1][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH3:21])=[CH:18][CH:19]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)N(C)c1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 90 °C
Yield: 31.2 %

Procedure:
A mixture of (2-methyl-quinazolin-4-yl)-(N-methyl-4-acetamido-phenyl)-methylamine (103 mg, 0.321 mmol) in 3 mL of methanol and 3 mL of 2N NaOH was heated at 90° C. for 4 h. The reaction mixture was cooled to room temperature and diluted 25 mL of ethyl acetate. It was washed with saturated NaHCO3, and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (40% ethyl acetate/hexane) to give the title compound (28 mg, 0.10 mmol, 31%). 1H NMR (CDCl3): 7.71 (m, 1H), 7.50 (ddd, J=8.4, 6.9, 1.5, 1H), 6.93-7.11 (m, 4H), 6.60 (m, 2H), 3.84 (s, broad, 1H), 3.57 (s, 3H), 2.87 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=O.[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH:20]([NH2:22])[CH3:21])=[CH:12]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:13]([CH:20]([NH:22][C:8](=[O:10])[CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH3:21])=[CH:12]1
Reactant: O=C(O)CCc1ccco1
Reactant: CC(N)c1csc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(NC(=O)CCc1ccco1)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.9 %

Procedure:
3-(2-Furyl)propionic acid (368 mg), 1-(benzothiophen-3-yl)ethylamine (443 mg), N-ethyl-N′-dimethylaminopropylcarbodiimide hydrochloride (575 mg), 1-hydroxybenzotriazole (405 mg), and triethylamine (304 mg) were added to dehydrated dimethylformamide (DMF, 15 mL), and stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 628 mg of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[CH2:23]([O:25][C:26](=[O:31])[CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:29][C:28]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1)([CH3:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:31]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CCOC(=O)C=C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292 μL, 0.00210 mol) were dissolved in DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the product was extracted with MTBE several times. The combined extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (0-60% EtOAc/Hexanes) to afford ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): δ □8.37 (d, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); MS (ES): 443 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH:13]([NH:23]C(=O)OC(C)(C)C)[C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15].Cl>C(Cl)(Cl)Cl.CO.O1CCOCC1>[NH2:23][CH:13]([C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[CH2:12][N:3]1[C:4](=[O:11])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)NC(CN1C(=O)c2ccccc2C1=O)C(C)(C)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(c1ccccc1)C(N)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1,1-dimethylethyl {1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-methyl-2-phenylpropyl}carbamate (723 mg, 1.77 mmol) in CHCl3:MeOH (10:1, 55 mL) at RT was added 4M HCl in dioxane (10 mL). After stirring for 3 h at RT, the reaction solution was concentrated to a white solid (quant.): LCMS (ES) m/z 309 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](O)=[O:16])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:35]([NH2:37])[CH3:36]>>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([C:15](=[O:16])[NH:37][CH2:35][CH3:36])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:10]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(-c2nn(Cc3ccccc3)c(=O)c(C(=O)O)c2-c2ccc(OC)cc2)cc1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1c(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn(Cc2ccccc2)c1=O
Yield: 59 %

Procedure:
Using 2-benzyl-5,6-bis(4-methoxyphenyl)-4-carboxy-2H-pyridazin-3-one and ethylamine hydrochloride as starting materials, the procedures of Example 22 were repeated likewise, whereby the title compound was obtained in a yield of 59.0%.
Reaction SMILES: O=[C:2]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20].C[Si](C)(C)O[Si](C)(C)C>C(Cl)Cl>[S:20]=[C:2]([NH:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)NCC(F)(F)F
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C[Si](C)(C)O[Si](C)(C)C
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=S)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.21 h
Yield: 95.3 %

Procedure:
To a stirred solution of (R)-tert-butyl 1-oxo-1-(2,2,2-trifluoroethylamino)propan-2-ylcarbamate (100 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added P2S5 (24 mg, 0.11 mmol) and hexamethyldisiloxane (HMDO) (0.13 mL, 0.59 mmol) at room temperature and the mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature and another portion of P2S5 (24 mg, 0.11 mmol) was added and the resulting mixture was refluxed for 18 h. The volatiles were evaporated, pentane (25 mL) was added to the residue and stirred for 10-15 min. The pentane layer was decanted, concentrated in vacuo and the residue was passed through a short silica pad eluting with pentane followed by CH2Cl2 to give the title compound as colorless liquid (30 mg, 30%): 1H NMR (400 MHz, DMSO-d6) δ 10.27 (t, J=5.4 Hz, 1H), 7.00 (d, J=6.8 Hz, 1H), 4.57-4.35 (m, 3H), 1.32 (s, 9H), 1.25 (d, J=7.6 Hz, 3H); ESIMS m/z 286.2 ([M+H]+); IR (thin film) 3233, 1683, 1257 cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17].CC1C(/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=C(OC)C(OC)=C(OC)C=1OC>>[CH3:1][C:2]1[C:7](/[CH:8]=[C:26](\[CH3:25])/[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14][CH3:15])[C:3]=1[O:16][CH3:17]
Reactant: CCOC(=O)/C=C/c1c(C)c(OC)c(OC)c(OC)c1OC
Reactant: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Product: CCOC(=O)/C(C)=C/c1c(C)c(OC)c(OC)c(OC)c1OC

Procedure:
Compound 8b was prepared from 7 (0.569 g, 2.37 mmol) as described above for 8a to give 0.674 g (2.08 mmol, 88%) of the product as a yellow oil following flash chromatography (1:3 EtOAc:hexanes).
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28]C)=[O:27])=[CH:22][C:21]=2[CH3:30])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCOCC1>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=[O:27])=[CH:22][C:21]=2[CH3:30])[CH2:14][CH2:15]1)=[O:9])([CH3:5])([CH3:6])[CH3:4]
Reactant: COC(=O)c1ccc(OCCCC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1OCCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 92 %

Procedure:
2M NaOH solution (1.25 ml, 2.5 mmol) was added to 4-[3-(4-methoxycarbonyl-2-methyl-phenoxy)-propyl]-piperidine-1-carboxylic acid tert-butyl ester from Example E68.2 (340 mg, 0.87 mmol) in dioxan (10 ml) and the mixture was heated at 60° C. for 20 h. 2M NaOH solution (5 ml, 10 mmol) was added and the mixture was heated at 60° C. for 20 h then concentrated in vacuo. The residue was purified by flash chromatography on silica gel through an isolute (eluant; 1% acetic acid:9% methanol:90% dichloromethane) to yield the title compound (303 mg, 92%).
Reaction SMILES: C([C@@H]1COC(=O)N1[C:14]([C@@H:16]1[CH2:28][CH2:27][C:19]2(OCC(C)(C)C[O:20]2)[CH2:18][C@H:17]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[F:35])=[O:15])C1C=CC=CC=1.[OH:36]O.[Li+].[OH-].Cl.C1(NC2CCCCC2)CCCCC1>C1COCC1>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C@@H:17]1[CH2:18][C:19](=[O:20])[CH2:27][CH2:28][C@H:16]1[C:14]([OH:15])=[O:36]
Reactant: OO
Reactant: CC1(C)COC2(CC[C@@H](C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)[C@H](c3ccccc3F)C2)OC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC[C@@H](C(=O)O)[C@H](c2ccccc2F)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The product from step 1 was dissolved in THF (200 mL) and cooled to 0° C. in an ice bath. Hydrogen peroxide (22.6 mL, 35%, 258 mmol), followed by LiOH (4.12 g, 172 mmol in 40 mL water) were added, and the mixture was allowed to warm to rt and stirred overnight to afford the acid intermediate [HPLC/MS: 323.2 (M+1); Rt=2.97 min]. To this solution was added aqueous HCl (21.5 mL, 12M) and the reaction was aged at 60° C. overnight. The reaction was cooled to rt and the organic phase was separated. The aqueous phase was extracted with EtOAc (200 mL). The organic portions were combined and dried with MgSO4, filtered and concentrated. The resulting crude product was dissolved in EtOAc (300 mL) and N-cyclohexylcyclohexanamine (18.9 mL, 95 mmol) was added over 2 min. The resulting slurry was aged for 1 h and filtered. The wet cake was washed with EtOAc (50 mL×4) and air dried on a fritted funnel. The salt was then suspended in aq NaHSO4 (200 mL, 2N) at rt and aged overnight. The reaction was extracted with EtOAc (200 mL), washed with water and brine, dried (MgSO4), filtered and concentrated to afford the title compound. HPLC/MS: 237.1 (M+1); Rt=2.13 min.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:14])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:24])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:24][C:2]1[C:7]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:6]([CH3:14])[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1c(C)ncnc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1c(C)ncnc1Cl

Procedure:
30.6 g (0.16 mol) of ethyl (4-hydroxy-6-methylpyrimidin-5-yl)acetate, 17.8 g (0.18 mol) of triethylamine and 263.2 g (1.72 mol) of phosphorus oxychloride were heated at reflux for 4 hours. The excess phosphorus oxychloride was stripped off, the residue was taken up in dichloromethane, and the mixture was added dropwise to 500 ml of sodium bicarbonate solution and neutralized by addition of solid sodium bicarbonate. The organic phase was separated off, dried and concentrated to give 30.4 g (88.5% of theory) of a dark oil which was reacted further without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2C2C(OC)=CC=CC=2OC)C2CCCCC2)CCCCC1.Br[C:47]1[CH:54]=[CH:53][C:50]([CH:51]=[O:52])=[C:49]([OH:55])[C:48]=1[F:56]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[F:56][C:48]1[C:49]([OH:55])=[C:50]([CH:51]=[O:52])[CH:53]=[CH:54][C:47]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Br)c(F)c1O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.7 %

Procedure:
(4-Fluorophenyl)boronic acid (33.2 g), 2M aqueous sodium carbonate solution (237 mL), palladium (II) acetate (2.49 g) and dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (9.74 g) were added to a solution of 4-bromo-3-fluoro-2-hydroxybenzaldehyde (34.6 g) in DME (350 mL) at room temperature. The mixture was stirred at 100 C under argon atmosphere for 16 hours. The mixture was cooled to room temperature. Water (700 mL) was added to the reaction mixture. The mixture was concentrated in vacuo to remove DME. The precipitate was collected by filtration and washed with water. The aqueous filtrate was set aside for further purification. Then the solid was washed with ethyl acetate. The solid was added to a mixture of ethyl acetate and 1M hydrochloric acid. The mixture was stirred at room temperature for 1 hour and filtrated through celite. The filtrate was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (20.6 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:13])[CH:9]=2)[CH:4]=1.[C-:14]#[N:15].[K+]>CC#N>[F:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([CH2:2][C:14]#[N:15])[CH:12]=[CH:11]2
Reactant: [C-]#N
Reactant: Fc1ccc2cc(CBr)ccc2c1
Agent: [K+]
Solvent: CC#N
Product: N#CCc1ccc2cc(F)ccc2c1
Yield: 75.7 %

Procedure:
To a mixture of 2-bromomethyl-6-fluoro-naphthalene (1.5 g, 5.9 mmoL) in CH3CN (30 mL) was added KCN (1.16 g, 17.8 mmoL). The reaction mixture was heated at reflux for 6 h before being concentrated. To the residue was added diethyl ether (100 mL) and H2O (15 mL). The organic layer was separated, dried and concentrated. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane=1:10) to afford the (6-fluoro-naphthalen-2-yl)-acetonitrile (0.88 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=2[C:16]#[N:17])[CH2:8][CH2:7]1)=[O:5].C(=O)(O)O.[NH2:31][C:32]([NH2:34])=[NH:33]>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([CH2:12][O:13][C:14]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:15]=2[C:16]([NH2:17])=[N:33][C:32]([NH2:34])=[N:31]3)[CH2:10][CH2:11]1)=[O:5]
Reactant: N=C(N)N
Reactant: N#Cc1c(F)cccc1OCC1CCN(C(=O)c2ccccc2Cl)CC1
Agent: O=C(O)O
Product: Nc1nc(N)c2c(OCC3CCN(C(=O)c4ccccc4Cl)CC3)cccc2n1
Yield: 29 %

Procedure:
The cyclization of 2-[1-(2-chlorobenzoyl)-piperidin-4-ylmethoxy]-6-fluoro-benzonitrile (219 mg, 0.6 mmol) and guanidine carbonate was carried out using Method Z to afford 70.6 mg of title compound (29% yield). 1HNMR (400 MHz, DMSO-d6) δ 7.52 (m, 1H), 7.43 (m, 3H), 7.36 (t, J=8.4 Hz, 1H), 7.2 (m, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.57 (t, J=7.2 Hz, 1H), 6.0 (br s, 2H), 4.56 (br d, J=12 Hz, 1H), 4.03 (d, J=6 Hz, 2H), 3.28 (m, 1H), 3.05 (m, 1H), 2.85 (t, J=12.8 Hz, 1H), 2.23 (m, 1H), 1.91 (m, 1H), 1.72 (t, J=13.6 Hz, 1H), 1.33 (m, 2H). MS m/z (ESI) 412 (M−H)+.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:29][CH:28]([N:30]=[C:31]=[O:32])[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([CH2:35][NH2:36])[OH:34]>C1COCC1>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:17])([F:18])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH:28]([NH:30][C:31]([NH:36][CH2:35][CH2:33][OH:34])=[O:32])[CH2:29]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N=C=O)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: NCCO
Solvent: C1CCOC1
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(NC(=O)NCCO)C3)ccc2n1CC1CCC(F)(F)CC1
Yield: 43.9 %

Procedure:
Following the same procedure in Example 105, Step A, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(3-isocyanatoazetidin-1-yl)sulfonyl]-1H-benzimidazole (0.095 mmol) and ethanolamine (12 uL, 12 mg, 0.19 mmol) in THF (6.0 mL). The crude product was purified by MPLC using EtOAc/MeOH (20:1) on silica gel to give 22 mg (44%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.49-1.65 (m, 2 H), 1.68 (s, 9 H), 1.70-1.86 (m, 4 H), 2.02-2.14 (m, 2 H), 2.19-2.36 (m, 1 H), 3.13 (t, J=5.57 Hz, 2 H), 3.48 (t, J=5.57 Hz, 2 H), 3.64 (dd, J=8.50, 6.35 Hz, 2 H), 3.99 (t, J=8.11 Hz, 2 H), 4.17-4.27 (m, 1 H), 4.55 (d, J=7.42 Hz, 2 H), 7.93 (dd, J=8.79, 1.76 Hz, 1 H), 8.06 (d, J=8.79 Hz, 1 H), 8.17 (d, J=1.37 Hz, 1 H); MS (ESI) (M+H)+=528.3; Anal. Calcd for C24H35F2N5O4S+0.90 TFA+1.0H2O+0.10 EtOAc (658.29): C, 47.99; H, 5.93; N, 10.64. Found: C, 47.99; H, 5.95; N, 10.68.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.O[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1>O>[CH:1]([O:3][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)=[O:2]
Reactant: O=C(O)c1ccc(CO)cc1
Reactant: O=CO
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=COCc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Formic acid (1.24 ml) and acetic anhydride (0.62 ml) were mixed and stirred at 50° C. for 30 minutes. This solution was cooled to 0° C., added with 4-hydroxymethylbenzoic acid (500 mg) and stirred at room temperature for 4.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 536 mg of the title compound. Yield: 91%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[CH:9]1(B(O)O)[CH2:11][CH2:10]1.N1C=CC=CC=1C1C=CC=CN=1.C([O-])([O-])=O.[Na+].[Na+].[NH4+].[Cl-]>ClCCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]([CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(Br)cc[nH]1
Reactant: OB(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Product: O=c1cc(Br)ccn1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask charged with a stir bar, 4-bromo-1H-pyridin-2-one (1.80 g), cyclopropylboronic acid (2.00 g), Cu(O2CCH3)2 (2.00 g), 2,2′-bipyridine (1.70 g), Na2CO3 (2.47 g), and 1,2-dichloroethane (75 mL) was heated to 70° C. The mixture was stirred at this temperature in air overnight. Then, further portions of cyclopropylboronic acid (0.50 g) and Na2CO3 (0.55 g) were added and the mixture was stirred at reflux temperature for another 4 h. After cooling to ambient temperature, aqueous NH4Cl solution was added and the resultant mixture was extracted with dichloromethane. The combined organic extracts were dried (MgSO4) and the solvent was evaporated. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 50:50→35:65) to afford the title compound as an oil that crystallized on standing. Yield: 0.82 g (37% of theory); Mass spectrum (ESI+): m/z=214/216 (Br) [M+H]+.
Reaction SMILES: [C:1]([C:4]([CH2:21][C:22]#[C:23][CH:24]([O:30]C(=O)C)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])C(OCC)=O)(=[O:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([CH:4]([CH2:21][C:22]#[C:23][CH:24]([OH:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CCCCCC(C#CCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OCC)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C#CCC(CCCCCCC(=O)O)C(C)=O
Yield: 36.1 %

Procedure:
A solution of diethyl 2-acetyl-2-(4-acetoxy-2-nonyn-1-yl)azelate (59.7 g., 0.128 mole) and sodium hydroxide (30 g., 0.75 mole) in water (200 ml.) and methanol (800 ml.) is heated at 60° for 16 hours. Most of the methanol is then distilled at reduced pressure and the residue is dissolved in water. The solution is acidified to Congo Red with hydrochloric acid and the oily product taken up in ether and dried over sodium sulfate. Evaporation of the ether leaves 41.1 g. of the crude product as a reddish viscous oil. The product is purified by chromatography on 650 g. of silica gel with 2% methanol in chloroform as eluant. Fifteen grams of pure 8-acetyl-12-hydroxy-10-heptadecynoic acid is obtained as a yellow viscous oil; pmr (CDCl3) δ 0.90 (3H,t), 2.20 (3H,s CH3CO), 4.37 (1H,t HCO).