Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]([C:5](=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=C(Cl)[C:11]=1[Cl:17])[C:6](O)=O)#[N:4].S([CH2:28][N+:29]#[C-])(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH2:32]([Cl:34])Cl>CO.O>[Cl:17][C:11]1[C:32]([Cl:34])=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[C:5]([C:3]#[N:4])=[CH:6][NH:29][CH:28]=1
Reactant: N#CC(=Cc1cccc(Cl)c1Cl)C(=O)O
Reactant: ClCCl
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1c[nH]cc1-c1cccc(Cl)c1Cl
Reaction time: 0.33 h
Yield: 99 %

Procedure:
12.62 g (225.0 m mol) of potassium hydroxide was dissolved in 80 ml of methanol. While being cooled at a temperature 0° to 10° C., the solution was fed with 12.10 g (50.0 m mol) of alpha-cyano-2,3-dichlorocinnamic acid and the mixture was stirred for 20 min. in the same temperature range. A solution of 10.25 g (52.5 m mol) of tosyl methylisocyanide in 70 ml of methylene chloride was added dropwise, at a temperature from 0° to 5° C., to the above mixture. The reaction mixture was then stirred for 30 min. at the same temperature to complete the reaction. Then, to the reaction mixture 50 ml of water was added and was neutralized to pH 8 by 10% HCl. From the neutralized mixture, methylene chloride and methanol was distilled off under reduced pressure, then, 100 ml of water was further added thereto and the mixture was stirred for 30 min. to precipitate crystals. The crystals were filtered off and washed with water and dried. 11.73 g of 3-(2,3-dichlorophenyl)-4-cyanopyrrole was obtained. Yield 99.0%, Melting point 152°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[CH:35]1([C:38]([N:24]2[CH2:23][CH2:22][N:21]([C:18]3[CH:19]=[CH:20][C:15]([C:7]4[NH:6][C:5](=[O:27])[C:4]5[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=5[O:2][CH3:1])[N:8]=4)=[CH:16][CH:17]=3)[CH2:26][CH2:25]2)=[O:39])[CH2:37][CH2:36]1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)C5CC5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol), and cyclopropane carbonyl chloride (0.03 mL, 0.36 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the material was purified by flash chromatography on silica gel eluting with 0% to 50% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2 to afford the title compound (0.100 g, 63%). 1H NMR (300 MHz, DMSO-d6): δ 11.78 (s, 1H), 8.12 (d, J=8.9 Hz, 2H), 7.04 (d, J=9.2 Hz, 2H), 6.63-6.74 (m, 1H), 6.39-6.52 (m, 1H), 3.73-3.95 (m, 8H), 3.51-3.73 (m, 2H), 3.21-3.49 (m, 4H), 1.93-2.10 (m, 1H), 0.56-0.83 (m, 4H). APCI MS m/z 435 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15]I>COCCOC>[CH3:15][C:9]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:13][CH2:12][CH2:11][C:10]1=[O:14]
Reactant: CI
Reactant: O=C1CCCC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(c2ccccc2)CCCC1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a slurry of 60% NaH (125 mg, 3.12 mmol) in DME (3571 μL) at 0° C. was added 2-phenylcyclopentanone (500 mg, 3.12 mmol). After stirring for 1 h, MeI (898 μL, 14.36 mmol) was added, and the solution heated to reflux for 2 h. The reaction was poured onto ice and extracted 3 times into Et2O. The organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Applied to Silica gel and eluted with an EtOAc/Hex gradient to afford 2-methyl-2-phenylcyclopentanone (401.7 mg, 2.305 mmol, 73.9% yield). LC-MS (M+H)+=175.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.29-7.37 (4H, m), 7.20-7.24 (1H, m), 2.54 (1H, dt, J=12.51, 6.26 Hz), 2.34 (2H, t, J=7.63 Hz), 1.82-2.05 (3H, m), 1.38 (3H, s).
Reaction SMILES: [O:1](C(O)CCC)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:24][C:25]1[CH:26]=[C:27]([N:32]2[C:37](=[O:38])[C:36](Br)=[C:35]([Br:40])[CH:34]=[N:33]2)[CH:28]=[CH:29][C:30]=1[F:31].[CH2:41]1[CH2:45][O:44][CH2:43][CH2:42]1>>[F:24][C:25]1[CH:26]=[C:27]([N:32]2[C:37](=[O:38])[C:36]([O:44][CH2:43][CH2:42][C@H:41]([O:1][Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3])[CH3:45])=[C:35]([Br:40])[CH:34]=[N:33]2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(F)c(F)c1
Reactant: C1CCOC1
Reactant: CCCC(O)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: C[C@H](CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a stirred, 0° C. solution of the product from Example 545B (3.4 g, 10 mmol) in THF (20 mL) was added 1M sodium bis(trimethylsilyl)amide in THF (12 mL, 12 mmol). The reaction mixture was stirred at room temperature for 0.5 hours, then it was transferred to a stirred, −30° C. solution of 2-(3,4-difluorophenyl)-4,5-dibromo-3(2H)-pyridazinone (3.66 g, 10 mmol) in THF (100 mL). The reaction mixture was stirred at −30° C. for 1 hour, then overnight while warming to room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was washed with brine (2×20 mL), then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 90:10 hexane/ethyl acetate) to provide the title intermediate (2.5 g, 51%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>CCO>[C:8]([C:7]1[C:6]([CH3:10])=[C:5]([CH:11]([OH:12])[CH2:13][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@@H:23]2[CH2:27][OH:28])[CH:4]=[CH:3][C:2]=1[F:1])#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: Cc1c(C2CO2)ccc(F)c1C#N
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2CO)ccc(F)c1C#N
Temperature: 150 °C

Procedure:
6-Fluoro-2-methyl-3-(oxiran-2-yl)benzonitrile (prepared as described above for I-17A and I-17B, Method 1, Steps A-C) (4.80 g, 27.1 mmol) and (R)-4-N-BOC-2-hydroxymethyl-piperazine (commercially available, e.g. from Acesys Pharmatech, catalog #A1612R; and also described in J. Org. Chem., 2007, 72(22), p. 8591-8592) (8.79 g. 40.6 mmol) were suspended in EtOH (30 mL) and heated in a microwave apparatus at 150° C. for 1 h. The reaction mixture was cooled and evaporated to dryness. The residue was purified by chromatography through a 330 g ISCO Redi-sep column eluting with ethyl acetate to 5% MeOH/ethyl acetate gradient to yield the title compound. LC-MS: M+1=394;
Reaction SMILES: Br[C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[OH:20][C:21]([CH3:27])([C:25]#[CH:26])[CH2:22][C:23]#[N:24]>>[C:23]([CH2:22][C:21]([OH:20])([CH3:27])[C:25]#[C:26][C:2]1[C:3]([F:19])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1)#[N:24]
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1OCC2
Reactant: C#CC(C)(O)CC#N
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)CC#N
Yield: 30 %

Procedure:
Similar to as described in General Procedure G, 10-bromo-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with 3-hydroxy-3-methylpent-4-ynenitrile to give the titled compound as a brown solid (70 mg, 30%).
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[NH:8]2.Cl.CN(C)CCCN=C=NCC.[N:27]1([C:33]2[N:34]=[C:35]([CH2:40][C:41]([O-])=[O:42])[NH:36][C:37](=[O:39])[CH:38]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+].O>CN(C)C=O.N1C=CC=CC=1>[F:14][CH:2]([F:1])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([CH3:13])[N:8]2[C:41](=[O:42])[CH2:40][C:35]1[NH:36][C:37](=[O:39])[CH:38]=[C:33]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[N:34]=1
Reactant: CC1Cc2c(cccc2OC(F)F)N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC1Cc2c(OC(F)F)cccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.4 %

Procedure:
125 mg of 4-difluoromethoxy-2-methyl-2,3-dihydro-1H-indole (reference example 11d) and 192.7 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 196.8 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (obtained in step 2d of example 1d) in 6 ml of N,N-dimethylformamide and 6 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then 25 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with a 0.1N hydrochloric acid solution, water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol (95/05: v/v), so as to give 220 mg of 2-{2-[4-(difluoromethoxy)-2-methyl-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one.
Reaction SMILES: [CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](Cl)=[O:26].O>C1COCC1>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([N:11]([C@@H:2]([CH3:1])[C@@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:12])=[O:26]
Reactant: O=C(Cl)CCCCCl
Reactant: CN[C@@H](C)[C@@H](O)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]([C@@H](O)c1ccccc1)N(C)C(=O)CCCCCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
To a magnetically stirred solution of (1S,2S)-pseudoephedrine (60 g, 363.1 mmol) in THF (600 mL) at room temperature was added triethylamine (65.4 mL, 472 mmol) in one portion. The resulting white suspension was cooled to 0° C. A solution of 5-chloropentanoyl chloride (49 mL, 381 mmol) in THF (130 mL) was added dropwise to the mixture over 45 min using an addition funnel. The mixture was then allowed to stir at 0° C. for 30 min. H2O (40 mL) was added and the resulting mixture was concentrated to ˜10% of the original volume. The resulting solution was partitioned between H2O/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (600 mL). The combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to furnish the crude product as pale yellow oil. The crude amide was purified by flash chromatography (ISCO; 3×330 g column; CH2Cl2 to 5% MeOH/CH2Cl2) to provide the product as a clear, viscous oil. The residual MeOH was removed through azeotroping with toluene (3×100 mL) to provide 5-chloro-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpentanamide (96.2 g, 339 mmol, 93%). LCMS (m/z=266.0)
Reaction SMILES: [H-].[Na+].[N:3]1[N:4]([CH2:8][CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:5]=[CH:6][CH:7]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:38][C:35]([F:36])([F:37])[O:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:16]=[CH:17][C:12]([CH2:11][O:10][CH2:9][CH2:8][N:4]4[N:5]=[CH:6][CH:7]=[N:3]4)=[CH:13][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(C=Cc2nc(CCl)co2)cc1
Reactant: Oc1ccc(COCCn2nccn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(COCCn4nccn4)cc3)co2)cc1
Reaction time: 0.25 h

Procedure:
25 mg (1.0 mmol) 95% Sodium hydride were given to a solution of 219 mg (1.00 mmol) 4-(2-[1,2,3]triazol-2-yl-ethoxymethyl)-phenol in 5.0 ml DMF and stirred for 15 min. 304 mg (1.00 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethoxy-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 20 ml water the resulting precipitate was washed twice with 10 ml water, 2×10 ml methanol, diethyl ether and dried at 45° C. in vacuum. Yield 254 mg (52%) colorless powder.
Reaction SMILES: [O:1]=[S:2]1(=[O:26])[CH:7]=[CH:6][N:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]3[CH2:19][C@H:18]([C:20](OC)=[O:21])[O:17][C:16]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[NH3:27]>CO>[O:26]=[S:2]1(=[O:1])[CH:7]=[CH:6][N:5]([C:8]2[C:9]([F:25])=[CH:10][C:11]([N:15]3[CH2:19][C@H:18]([C:20]([NH2:27])=[O:21])[O:17][C:16]3=[O:24])=[CH:12][C:13]=2[F:14])[CH2:4][CH2:3]1
Reactant: N
Reactant: COC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3C=CS(=O)(=O)CC3)c(F)c2)C(=O)O1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
A solution of methyl (5R)-3-[4-(1,1-dioxido-2,3-dihydro-4H-1,4-thiazin-4-yl)-3,5-difluorophenyl]-2-oxo-1,3-oxazolidine-5-carboxylate (Step 3, 0.090 g, 0.23 mmol) in methanol (2 mL) is treated with a solution of ammonia in methanol (2 mL of a 2.0M solution). The mixture is stirred for 1.5 h and concentrated. The residual solids are washed with methanol to provide 75 mg (86%) of the title compound as a white solid, MS (m/z) for C14H13F2N3O5S: [M+H]+=374; 1H NMR (300 MHz, d6-DMSO): δ 3.33–3.39 (m, 2H), 3.99–4.06 (m, 3H), 4.26 (t, 1H), 5.04–5.09 (m, 1H), 5.48 (d, 1H), 6.93 (d, 1H), 7.50 (d, 2H), 7.65 (s, 1H), 7.90 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=2)[CH2:2][CH3:3].Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[O:21][N:20]=1>>[F:30][C:28]1[CH:29]=[C:24]([C:22]2[O:21][N:20]=[C:19]([CH2:18][N:5]3[C:6]4[C:11](=[C:10]([C:13]#[N:14])[C:9]([C:15]#[N:16])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:1][CH2:2][CH3:3])[N:23]=2)[CH:25]=[C:26]([F:31])[CH:27]=1
Reactant: CCCc1cc2c(C#N)c(C#N)ccc2[nH]1
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Product: CCCc1cc2c(C#N)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1

Procedure:
Synthesized as described in Example 4 from 2-propyl-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.75-7.62 (m, 4H), 5.94 (s, 2H), 3.06 (t, 2H), 1.77-1.65 (m, 2H), 0.95 (t, J=7.3 Hz, 3H): MS (ES) m/z 404 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:31])[CH:9]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([O:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[CH:25][NH:26]4)[CH:16]=[N:15]2)[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:3]1.[C:32](=O)([O-])[O-].[K+].[K+].[CH3:38][C:39]1([CH3:55])[O:43][C@@H:42](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:41][O:40]1>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:31])[CH:9]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([O:21][C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4[CH2:32][C@@H:42]3[CH2:41][O:40][C:39]([CH3:55])([CH3:38])[O:43]3)[CH:16]=[N:15]2)[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2COC(C)(C)O2)cc1
Reactant: CC(C)CC(C(=O)Nc1ccn(C)n1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CC(C(=O)Nc1ccn(C)n1)n1ncc(Oc2cccc3c2ccn3C[C@@H]2COC(C)(C)O2)cc1=O
Temperature: 90 °C
Yield: 21 %

Procedure:
A solution of 2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (34.0 mg, 0.0809 mmol) in N,N-dimethylformamide (1.0 mL) was treated with potassium carbonate (23.1 mg, 0.16 mmol) and toluene-4-sulfonic acid (S)-2,2-dimethyl-[1,3]dioxolan-4-yl ester (25.5 mg, 0.08 mmol). The resulting reaction mixture was heated at 90° C. overnight. At this time, the reaction mixture was allowed to cool to 25° C., concentrated in vacuo and was treated with a saturated aqueous ammonium chloride solution (2 drops). The reaction was then concentrated in vacuo onto silica gel. Silica gel column chromatography (AnaLogix 12 g, 1-5% methanol/methylene chloride) afforded 2-{4-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indol-4-yloxy]-6-oxo-6H-pyridazin-1-yl}-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide (9.0 mg, 21%) as a viscous brown oil.
Reaction SMILES: [F:1][CH:2](O)[CH2:3][CH2:4][F:5].[H-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4[CH2:31][C:32]([NH2:34])=[O:33])[N:18]=2)[CH:13]=[CH:14][C:15]=1F.[OH2:35]>CN(C=O)C>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:30]=[CH:29][CH:28]=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4[CH2:31][C:32]([NH2:34])=[O:33])[N:18]=2)[CH:13]=[CH:14][C:15]=1[O:35][CH:3]([CH2:4][F:5])[CH2:2][F:1]
Reactant: O
Reactant: NC(=O)Cn1ccc2c(-c3noc(-c4ccc(F)c(Cl)c4)n3)cccc21
Reactant: OC(F)CCF
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc2c(-c3noc(-c4ccc(OC(CF)CF)c(Cl)c4)n3)cccc21
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,3-difluoropropanol (62 mg) in DMF (2.4 ml) was added 60% NaH (19 mg) at −10° C., followed by stirring at −10° C. for 0.5 hour. To this reaction mixture was added 2-{4-[5-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (120 mg) at −10° C., followed by stirring at −10° C. for 3 hours. After adding water to the reaction solution, the reaction mixture was extracted with EtOAc, the organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5) to obtain 2-[4-(5-{3-chloro-4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (76.9 mg) as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=[C:9]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])[O:8]1.CCN(C(C)C)C(C)C.[C:40](Cl)(=[O:44])[CH:41]([CH3:43])[CH3:42].Cl>C(Cl)Cl>[F:24][C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[C:9]1[O:8][C:7]([CH2:6][CH2:5][CH2:4][NH:3][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:11]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])[N:10]=1
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)OC1(CCCN)c1ccccc1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NCCCC1(c2ccccc2)OC(c2cc(F)ccc2F)=NN1C(=O)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-oxadiazol-3(2H)-yl)-2-methylpropan-1-one dihydrochloride, prepared as in the above examples, (50 mg, 0.11 mmol) in anhydrous CH2Cl2 (1 mL) was added DIEA (95 μL, 0.54 mmol) followed by isobutyryl chloride (17 μL, 0.16 mmol). After stirring at room temperature for 16 hours the mixture was treated with 1N HCl (10 mL) and extracted with CH2Cl2 (2×10 mL). The combined organic phases were washed with brine (10 mL) then dried over Na2SO4 and concentrated. The residue was chromatographed (4:1 to 2:1 hexanes/EtOAc) to afford the product (31 mg, 62%) as a colorless gum. MS ESI (+) m/z 458.1 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 3H), 7.36 (m, 3H), 7.17 (m, 2H), 3.33 (m, 3H), 3.04 (m, 1H), 2.53 (m, 1H), 2.35 (m, 1H), 1.77 (m, 1H), 1.56 (m, 1H), 1.16 (m, 12H).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](O)(=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)O.S(=O)(=O)(O)O>C(O)(=O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:5]2[O:6][C:9](=[O:18])[CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: O=C(O)C(O)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C1Oc2ccc(O)cc2C1c1ccccc1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of hydroquinone (15 g), mandelic acid (15 g), acetic acid (95 cm3) and sulphuric acid (5 cm3) was stirred at ambient temperature before filtering off solid material. The solid was washed with water and dried to give 5-hydroxy-2-oxo-3-phenyl-2,3-dihydrobenzofuran (14 g, 65%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH:4]([OH:9])[CH2:5][CH2:6][CH2:7][CH3:8].[Cl-].[OH2:11].[CH:12]#[CH:13]>N1C=CC=CC=1>[C:12]([O:9][CH:4]([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][C:2]#[CH:1])(=[O:11])[C:13]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: C#C
Reactant: C#CCC(O)CCCC
Reactant: O
Agent: [Cl-]
Solvent: c1ccncc1
Product: C#CCC(CCCC)OC(=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a stirred solution of 63. g (0.50 moles) of 1-octyn-4-ol (Example 93) in 500 ml of pyridine is added 77 g (0.55 moles) of beazoyl chloride. After stirring for 1.5 hours the mixture is treated with 10 ml of water, allowed to stand for 15 minutes, and concentrated. A solution of the residue in ether is washed successively with ice-cold hydrochloric acid, water, sodium bicarbonate solution, and brine. The solution is dried over magnesium sulfate, filtered through Celite, and concentrated to give an oil, λ max. 3240 (terminal acetylene) and 1730 cm-1 (benzyloxy group).
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][SH:3].O.[I-:6].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH3:14].[OH-].[Na+]>O1CCCC1>[I-:6].[SH:3][CH2:2][CH2:1][S:4][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[CH3:14]
Reactant: SCCS
Reactant: C[n+]1ccccc1F
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[n+]1ccccc1SCCS
Temperature: 23 °C

Procedure:
To a mixture of 1,2-ethanedithiol (0.63 mL, 7.5 mmol), water (21 mL) and tetrahydrofuran (4 mL) were added simultaneously 2-fluoro-1-methylpyridinium iodide, described by G. B. Barlin and J. A. Benbow, J.C.S. Perkin II, 790 (1974), (0.90 g, 3.72 mmol) and 1N sodium hydroxide solution (5-6 mL) to keep the pH of the mixture between 6 and 7. When the addition of 2-fluoro-1-methylpyridinium iodide was completed, the reaction mixture was stirred at 23° C. while the pH was kept at 7.1 by the addition of the 1N sodium hydroxide solution. When the pH of the mixture was stabilized at 7.1, the solvents were evaporated under high vacuum until dryness. The solid was triturated in ether (3×10 mL) and in acetonitrile (2×8 mL). The ether solution was dried (MgSO4) and concentrated to give 0.10 g of N-methyl-2(1H)-pyridothione. The acetonitrile solution was dried (MgSO4) and concentrated to give 0.74 g of 2-(2-mercaptoethylthio)-1-methylpyridinium iodide and/or fluoride mixed with some inorganic salts; ir (KBr) νmax : 1617 (pyridinium) cm-1, 1Hmr (DMSO-d6) δ: 2.75-3.1 (m, 2H, CH2SH), 3.4-3.9 (m, CH2S and SH), 4.17 (s, 3H, CH3 on pyridinium), 7.6-9.2 (m, 4H, H's of pyridinium). The acetonitrile insoluble material (0.38 g) was 1,2-di(1-methylpyridinium-2-thio)ethane diiodide or/and difluoride or monoiodidemonofluoride mixed with some inorganic salts; 1Hmr (DMSO-d6) δ: 3.90 (4H, s, SCH2CH2S), 4.21 (6H, s, CH3 's on pyridinium), 7.7-9.1 (8H, m, H's of pyridiniums). The thiol was used without any further purification.