Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]([CH2:27][C:28]([O:30]CC)=[O:29])[CH2:22][CH2:21][CH2:20]3)[CH:10]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:21][CH2:20]3)[CH:10]=1
Reactant: CCOC(=O)CC1CCCc2cc(OCc3cccc(-c4c(C)cccc4C)c3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(C)c1-c1cccc(COc2ccc3c(c2)CCCC3CC(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.1 %

Procedure:
To a solution of ethyl (6-[(2′,6′-dimethylbiphenyl-3-yl)methoxy]-1,2,3,4-tetrahydronaphthalen-1-yl)acetate (0.15 g, 0.35 mmol) in a mixed solvent of ethanol (1 mL) and tetrahydrofuran (1 mL) was added 2 M aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.08 g, yield 57%) as colorless prism crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[C:5]#[N:6].[NH:11]([CH3:13])[CH3:12]>C1COCC1.CC(=O)OCC>[Cl:10][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([N:11]([CH3:13])[CH3:12])[N:9]=1)[C:5]#[N:6]
Reactant: CNC
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)c1cc(C#N)cc(Cl)n1
Temperature: 25 °C

Procedure:
A solution of 2,6-dichloroisonicotinonitrile (2.50 g, 14.5 mmol) in 2 N Me2NH in THF (20 mL) is stirred in a sealed vessel at 105° C. for 24 h. The dark suspension is cooled to rt, diluted with EA (200 mL), washed with water (2×50 mL) followed by sat. aq. NaHCO3-solution (50 mL), dried over Na2SO4, filtered and concentrated to give crude 2-chloro-6-dimethylamino-isonicotinonitrile; LC-MS: tR=0.96 min, [M+1]+=182.00. This material is dissolved in dioxane (100 mL) and Pd(dppf) (120 mg, 0.147 mmol) is added. To this solution, MeZnCl (5.02 g, 43.4 mmol, 2 M solution in THF) is slowly added. The mixture is stirred at rt for 30 min, then at 75° C. for 16 h. The orange suspension is cooled to rt, diluted with EA (150 mL) and washed with water (2×50 mL). The aq. washings are basified by adding NaOH and the precipitate that forms is filtered off. The filtrate is extracted with DCM (3×70 mL). The combined org. extracts are dried over Na2SO4, filtered and concentrated. The crude product is purified by MPLC on silica gel eluting with EA containing methanol to give 2-dimethylamino-6-methyl-isonicotinonitrile (699 mg) as a brownish oil which slowly solidifies; LC-MS: tR=0.50 min, [M+1]+=162.05.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[CH3:18][N:19]([CH3:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S([O-])([O-])(=O)=O.[Mg+2]>[N+](C)([O-])=O>[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N+:19]([CH3:26])([CH3:18])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccccc1
Reactant: COc1ccc(CO)cc1
Agent: F[Sb-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C[N+](C)(C)c2ccccc2)cc1
Yield: 70 %

Procedure:
13.81 g (0.1 mol) of 4-methoxybenzylalcohol and 35.78 g (0.1 mol) of N,N-dimethylaniline hexafluoroantimonate were dissolved in 100 g of nitromethane and, after the addition of 12.04 g (0.1 mol) of magnesium sulfate, allowed to react at 80° C. for 4 hours. After the completion of the reaction, the mixture was filtered and the filtrate was concentrated. The precipitated white solid was washed with ether and dried to give the titled compound. Yield: 70%.
Reaction SMILES: [C:1](=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6])([CH3:3])[CH3:2].C1C(=O)N([Br:20])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[C:1](=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH2:8][Br:20])=[O:6])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C(=O)OC)=C(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C(=O)OCBr)=C(C)C
Yield: 109.7 %

Procedure:
A mixture of 26. 4 grams (0.15 mol) of dimethyl isopropylidenemalonate and 27.5 grams (0.15 mol) of n-bromosuccinimide were stirred in 150 mL carbon tetrachloride containing 1.0 grams benzoyl peroxide. The mixture was refluxed for 16 hours under nitrogen. The reaction was cooled in ice and the succinimide was filtered off and washed with carbon tetrachloride. The solvent was removed under reduced pressure to yield 41.3 grams of impure bromomethyl methyl isopropylidenemalonate as an oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[F:29][C:30]([F:47])([F:46])[O:31][C:32]1[CH:45]=[CH:44][C:35]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[NH2:43])=[CH:34][CH:33]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][C:35]2[CH:44]=[CH:45][C:32]([O:31][C:30]([F:29])([F:46])[F:47])=[CH:33][CH:34]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1Oc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (HVB01062, 1.19 g, 5.2 mmol) was dissolved in anhydrous DCM (40 ml), and stirred under nitrogen. To this was added N N-4-dimethylaminopyridine (cat.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.0 g, 4.2 mmol) and TEA (0.84 ml). Stirred for 30 min. 2-(4-Trifluoromethoxy-phenoxy)-phenylamine (HVB01053, 1.4 g, 5.2 mmol) was added and stirred under nitrogen for 20 h. Diluted with DCM, washed with HCl (1M, 20 ml), Sodium hydrogen carbonate (sat. 20 ml), and brine (20 ml). Organic layers combined and dried over anhydrous magnesium sulphate, and evaporated in-vacuo. The crude mixture was purified using flash chromatography (DCM/hexane, 0 to 100%), to afford a yellow solid, 1.59 g, 57%. m.p. 45-48° C., Rf. 0.65 (DCM), 1HNMR: (CDCl3, 270 MHz) δ 1.44 (9H, s, CH3), 1.67 (2H, td, J=13.4, 4.4 Hz, CH2), 1.80 (2H, dd, J=1.8 Hz, CH2), 2.36 (1H, m, CH), 2.74 (2H, t, J=11.9 Hz, CH2N), 4.12 (2H, d, J=11.6 Hz, CH2N), 6.85 (1H, dd, J=6.7, 1.5 Hz, Ar HD), 7.03 (2H, d, Ar HF), 7.04 (1H, m, Ar HB), 7.13 (1H, td, J=1.5, 6.4 Hz, Ar HC), 7.20 (2H, d, J=1.5, 6.4 Hz Ar HF), 7.64 (1H, s, NH), 8.40 (1H, d, J=8.2 Hz, Ar HA.
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([O:17]CC)=[O:16])[CH:11]=2)[N:6]=1>C(O)C>[CH3:3][NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=[O:16])[CH:11]=2)[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(NC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CNc1ccc2cc(C(=O)O)ccc2n1
Temperature: 50 °C
Yield: 94.9 %

Procedure:
Aqueous sodium hydroxide (4 mL, 8 mmol, 2 N) was added to a solution of ethyl 2-(methylamino)quinoline-6-carboxylate (850 mg, 3.7 mmol) in ethanol (10 mL). The reaction was heated to 50° C. overnight. Ethanol was removed in vacuo and the residue was acidified to pH=5 with 1 N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dried under vacuum to give the title compound (710 mg, 96%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, δ): 8.26 (d, 1H), 7.96-7.93 (m, 2H), 7.50 (d, 1H), 7.43 (d, 1H), 6.81 (d, 1H), 2.91 (d, 3H).
Reaction SMILES: FC1C=C(C[C@H](C2C([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=CN=C(NCCOC)N=2)NC(=O)CN2C3CCCCC=3C(C(F)(F)F)=N2)C=C(F)C=1.Br[C:50]1[C:51]([C@@H:62]([NH:72][C:73](=[O:91])[CH2:74][N:75]2[C:83]3[C:82]([F:85])([F:84])[CH2:81][CH2:80][C:79]([F:87])([F:86])[C:78]=3[C:77]([CH:88]([F:90])[F:89])=[N:76]2)[CH2:63][C:64]2[CH:69]=[C:68]([F:70])[CH:67]=[C:66]([F:71])[CH:65]=2)=[N:52][C:53]([NH:56][CH2:57][CH2:58][N:59]([CH3:61])[CH3:60])=[N:54][CH:55]=1>>[F:90][CH:88]([F:89])[C:77]1[C:78]2[C:79]([F:87])([F:86])[CH2:80][CH2:81][C:82]([F:84])([F:85])[C:83]=2[N:75]([CH2:74][C:73]([NH:72][C@H:62]([C:51]2[C:50]([C:34]3[CH:35]=[CH:36][C:37]([F:43])=[C:38]([CH:42]=3)[C:39]([NH2:41])=[O:40])=[CH:55][N:54]=[C:53]([NH:56][CH2:57][CH2:58][N:59]([CH3:60])[CH3:61])[N:52]=2)[CH2:63][C:64]2[CH:65]=[C:66]([F:71])[CH:67]=[C:68]([F:70])[CH:69]=2)=[O:91])[N:76]=1
Reactant: CN(C)CCNc1ncc(Br)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1
Reactant: COCCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)n1
Product: CN(C)CCNc1ncc(-c2ccc(F)c(C(N)=O)c2)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)n1

Procedure:
The title compound (16B) was prepared according to the method presented for the synthesis of compound 11J of Example 11 utilizing 16A. 1H NMR (400 MHz, —CD3OD) δ 8.75 (d, J=7.4 Hz, 1H), 8.13 (s, 1H), 7.38 (m, 2H), 7.21 (dd, J=10.8, 8.4 Hz, 1H), 6.98-6.63 (m, 2H), 6.42 (m, 2H), 5.23 (d, J=7.6 Hz, 1H), 5.02 (q, J=16.8 Hz, 2H), 3.88 (m, 2H), 3.45 (t, J=5.5 Hz, 2H), 3.15-2.93 (m, 8H), 2.52 (m, 4H). MS (m/z) 743.60 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2[CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1.O[C:23]1C=CC2C3(C)CCN(C(OC(C)(C)C)=O)CC3OC=2C=1>>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH3:23])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]3[O:21][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(O)cc3OC2C1
Product: CC(C)(C)OC(=O)N1CCC2(C)c3ccc(I)cc3OC2C1

Procedure:
Synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate starting from tert-butyl 7-hydroxy-4a-methyl-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate. MS m/z 360 [M-tBu+H]+
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]([OH:25])=O.C(OC(Cl)=O)C(C)C.CN1CCOCC1.[CH3:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH2:44][NH2:45]>ClCCl>[CH3:41][C:42]([CH3:47])([CH3:46])[CH2:43][CH2:44][NH:45][C:23](=[O:25])[CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:2]1=[O:1]
Reactant: O=C(O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reactant: CC(C)(C)CCN
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)CCNC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.8 %

Procedure:
To a stirred solution of (2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetic acid (0.25 g, 0.74 mmol), isobutylchloroformate (0.11 mL, 0.81 mmol), N-methylmorpholine (0.09 mL, 0.81 mmol) in dichloromethane (10 mL) was added 3,3-dimethylbutylamine (0.11 g, 1.1 mmol). The solution was stirred at ambient temperature for 16 h, diluted with dichloromethane (10 mL) and washed with 2 M sodium carbonate (2×25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by flash chromatography with ethyl acetate in hexanes (30% to 50% gradient) to afford N-(3,3-dimethylbutyl)-2-(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)acetamide (0.13 g, 41%) as a colorless solid: mp 161-163° C.; 1H NMR (300 MHz, DMSO-d6) δ8.14 (dd, J=5.4, 5.4 Hz, 1H), 7.25 (dd, J=7.6, 7.6 Hz, 1H), 7.11 (d, J=6.9 Hz, 1H), 7.03-6.95 (m, 1H), 6.90 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.37 (s, 1H), 4.71 (ABq, 2H), 4.51-4.40 (m, 2H), 4.38-4.20 (m, 2H), 3.12-3.01 (m, 2H), 2.93 (t, J=8.6 Hz, 2H), 1.37-1.27 (m, 2H), 0.85 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ177.6, 166.3, 161.5, 160.9, 143.1, 132.7, 129.0, 123.8, 123.3, 121.3, 120.2, 119.8, 109.4, 92.8, 80.2, 72.5, 57.3, 43.2, 43.0, 35.9, 30.0, 29.7, 28.8; MS (ES+) m/z 421.2 (M+1).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>C(O)(=O)C.[Pd]>[N:1]1([C:6]2[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=2)[NH2:12])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-n2ccnc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1cccc(-n2ccnc2)c1

Procedure:
To 3-(1-imidazolyl)nitrobenzene (51.6 g, 0.27 mol) in acetic acid (500 ml) is added palladium catalyst (5 g 5% Pd on activated carbon) and the mixture is hydrogenated under pressure (Pstart : 4 bar) until the hydrogen uptake has ceased. The mixture is filtered through celite and the filtrate is evaporated to dryness to leave 2d as a light-brown oil. Yield: 40.4 g (93%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C@H:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:16])[C@H:10]([CH2:23][CH3:24])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH2:23]([C@H:10]1[C@H:11]([NH:14][C@H:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[CH2:12][CH2:13][NH:8][CH2:9]1)[CH3:24]
Reactant: CC[C@@H]1CN(Cc2ccccc2)CC[C@H]1N[C@@H](C)c1ccccc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: CC[C@@H]1CNCC[C@H]1N[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.5 %

Procedure:
To a solution of (3R,4R)-1-benzyl-3-ethyl-N—((S)-1-phenylethyl)piperidin-4-amine (679.2 mg, 2.106 mmol) in 1,2-dichloroethane (3.50 ml) at 0° C. was added 1-chloroethyl chloroformate (0.276 ml, 2.53 mmol) dropwise. After stirring for 20 minutes, the ice-bath was removed and the reaction was heated to reflux for 1 hr. The reaction was cooled to room temperature and concentrated under reduced pressure. Methanol (10.5 ml) was added, and the reaction was heated to reflux for 2 hrs. After removal of the solvent, the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding (3R,4R)-3-ethyl-N—((S)-1-phenylethyl)piperidin-4-amine (443 mg, 1.906 mmol, 91.0% yield) as a yellow oil. LCMS (Method E) m/z 233.3 ([M+H]+).
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:52]=[CH:51][C:42]2[CH:43]([OH:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:47])(=[O:46])[C:41]=2[CH:40]=1>>[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:52]=[CH:51][C:42]2[CH:43]([OH:50])[C:44]([CH3:49])([CH3:48])[S:45](=[O:46])(=[O:47])[C:41]=2[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1(C)C(O)c2ccc(Br)cc2S1(=O)=O
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: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc2c(c1)S(=O)(=O)C(C)(C)C2O

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 6-bromo-2,2-dimethyl-2,3-dihydro-1-benzothiophene-3-ol 1,1-dioxide (Intermediate 244), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[F:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CF)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CF)cc1
Yield: 93.9 %

Procedure:
To 200 ml of methanol, 8.68 g of methyl 4-(fluoromethyl)benzoate was dissolved, and 77 ml of aqueous solution of 1 N sodium hydroxide was added dropwise with stirring and cooling. The mixture was then stirred for 3.5 hours at room temperature. After the mixture was acidified with 1 N hydrochloric acid, the precipitated crystals were collected by filtration, and the filtrate was concentrated. The precipitated crystals were combined with the residue obtained by concentrating the filtrate, and water was added thereto. The mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to provide 7.47 g of the objective compound as colorless crystals. M.p. 192–194° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2cccnc21
Yield: 52 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbony)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 52% of theory. Colourless crystals, m.p. 146°-147.5° C. (acetonitrile).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([OH:13])=[O:12])=[CH:4][C:3]=2[O:2]1.S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc2c(c1)OCO2

Procedure:
To a solution of 3,4-methylenedioxyphenylacetic acid (10 g) in ethanol (100 ml) was added conc. sulfuric acid (3 ml). After being refluxed for 90 minutes, the mixture was concentrated in vacuo. The residue was dissolved in diethyl ether (150 ml). The solution was washed with 1M aqueous sodium bicarbonate solution and brine successively and dried over magnesium sulfate, and concentrated in vacuo to give ethyl 3,4-methylenedioxyphenylacetate (11.0 g) as an oil.
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:28][CH2:27][CH2:26][C@H:11]2[C:12]([NH:14][C@H:15]([C:23]([OH:25])=O)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:31][O:32][NH2:33]>>[CH3:31][O:32][NH:33][C:23](=[O:25])[C@H:15]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:14][C:12](=[O:13])[C@@H:11]1[CH2:26][CH2:27][CH2:28][N:10]1[S:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:29])=[CH:6][CH:5]=1)(=[O:9])=[O:8]
Reactant: CON
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: Cl
Product: CONC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)-L-prolyl-L-phenylalanine was coupled to O-methylhydroxylamine hydrochloride using the mixed anhydride procedure (as described in Greenstein, J. P. and Milton Wenitz, “Chemistry of the Amino Acids,” volume 2, pp. 978-979, Robert E. Krieger Publishing Co., Malabar, Fla. (1961)) to give the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:9](Cl)[Cl:10])=[CH:4][CH:3]=1.[OH-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[CH:9][Cl:10])=[CH:4][CH:3]=1
Reactant: Clc1ccc(C(c2ccc(Cl)cc2)C(Cl)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: ClC=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a 4-necked 2-liter flask are placed 500 g (1.56 mole) of 2,2-bis(p-chlorophenyl)-1,1-dichloroethane and 500 ml of dimethyl sulfoxide. A solution of 188 ml (2.34 mole) of 50% sodium hydroxide is added dropwise. The reaction mixture exotherms to 63° during the addition. After the addition, the reaction mixture is stirred for one hour and poured into ice-water. It is extracted with ether. The combined ether extracts are washed with water, saturated sodium chloride solution, and dried over sodium sulfate. Solvent is evaporated to give 311 g of a waxy solid. A portion of the crude product is recrystalized from hexane-ether to give a white solid, mp 65°-7°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:20][NH:21][C:22](=O)[O:23]C1C=CC=CC=1.O>CN(C)C=O>[CH3:20][NH:21][C:22]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:23]
Reactant: CNC(=O)Oc1ccccc1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 93.4 %

Procedure:
Sodium hydride (2.212 g, 55.30 mmol, 60% in oil) was suspended in N,N-dimethylformamide (100 ml), 5-benzyloxyindole (10.29 g, 46.09 mmol) was added thereto while stirred at room temperature, and the reaction mixture was stirred at room temperature for 40 minutes. The reaction mixture was cooled with an ice water bath, and phenyl N-methylcarbamate (8.360 g, 55.30 mmol) was added. After the reaction mixture was stirred for 30 minutes, the solution was stirred at room temperature for 2.5 hours. After water was added to the reaction mixture and the reaction mixture was stirred at room temperature for 1 hour, the obtained crystals were filtered off, then these crystals were sequentially washed with water and diethyl ether, and dried under aeration to yield the title compound (12.07 g, 43.06 mmol, 93.41%) as pale yellow crystals.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH2:15]C)=[O:13])=[CH:8][CH:7]=1)=[O:5].Cl>CO.CCOCC>[ClH:1].[NH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH:11]([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:18][CH:19]=1)=[O:5]
Reactant: CCOC(=O)C(C)Oc1ccc(C(=O)CN)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(C)Oc1ccc(C(=O)CN)cc1

Procedure:
A solution of ethyl 2-[4-(aminoacetyl)phenoxy]-propionate hydrochloride (2.0g.) in a mixture of methanol (150ml.) and a saturated solution of hydrogen chloride in ether (1ml.) was stirred and heated under reflux for 48 hours. The reaction mixture was then evaporated in vacuo and the residue was triturated with ether (50ml.) (dried over sodium wire) to give methyl 2-[4-(aminoacetyl)phenoxy]propionate hydrochloride which was isolated as a hygroscopic solid (1.3g.) having a satisfactory analysis; found: C, 50.0%; H, 5.9%, N, 4.9%; required (+ 3/4 mole H2O): C, 50.2%; H, 6.1%; N, 4.9%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([NH:15][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1ccc(Cl)cn1

Procedure:
The title compound was prepared by the same method as that described in Example 27, using 5-chloro-2-pyridinecarboxylic acid and t-butylamine.