Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([N+:26]([O-])=O)=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:8]=[C:9]([F:11])[CH:10]=1.O.NN>C(O)C.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:14])=[O:15])[C:6]=1[NH2:26]
Reactant: O=[N+]([O-])c1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cc(F)cc1OCCCl
Temperature: 60 °C

Procedure:
A mixture of 1-[3-(2-chloro-ethoxy)-5-fluoro-2-nitro-phenylmethanesulfonyl]-naphthalene (1.0 g, 2.36 mmoles) in ethanol (25 mL) was stirred under nitrogen in a round bottom flask at 60° C. 10% Pd/C was added, and the temperature was increased to 80° C. Hydrazine hydrate (2.0 mL) was added dropwise and the mixture was stirred at reflux for 3 hours. Reaction mixture was filtered off through Celite, and the solution was washed with H2O (3×), dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off white solid (0.91 g, 2.31 mmoles).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][CH2:9][C:2]1=2.[H-].[Na+].CN([CH:16]=[O:17])C.[CH3:18]I>C1(C)C=CC=CC=1.C(O)(C)C>[CH3:18][C:7]1([CH3:6])[CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:16]1=[O:17]
Reactant: O=C1CCCc2sccc21
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC1(C)CCc2sccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
6,7-Dihydrobenzo[b]thiophen-4(5H)-one (1.0 g, 6.6 mmol) in toluene (10 mL) was added drop-wise to NaH (60% dispersion in mineral oil, 1.32 g, 32.9 mmol) in toluene (5 mL). DMF (5 mL) was added and the reaction was stirred at room temperature for 1 hr. The mixture was cooled to 0° C., methyl iodide (4.67 g, 2.1 mL, 32.9 mmol) was added drop-wise and the solution was refluxed for 3 h. The mixture was cooled and carefully treated with iso-propanol. The product was extracted into diethyl ether (×3) and this was back extracted with water and saturated brine. The diethyl ether solution was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified on silica gel using a gradient elution of 0-75% ethyl acetate in 40-60 petroleum ether to afford the title compound as a yellow oil (0.375 g, 32%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][OH:32])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C@H:19]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([CH:31]=[O:32])[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a stirred solution of oxalyl chloride (2.21 mL, 25.4 mmol) in dichloromethane (120 mL) at −78° C. was added dimethyl sulfoxide (3.6 mL, 50.8 mmol) dropwise via syringe. The mixture was stirred at −78° C. for 10 minutes, and a solution of tert-butyl (2S,4R)-4-(benzyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (3.9 g, 12.69 mmol, Part A) in dichloromethane (30 mL) was added. The mixture was stirred at −78° C. for 15 minutes, and triethylamine (7.07 mL, 50.8 mol) was added. After 15 minutes, the reaction mixture was allowed to warm to 0° C. and stirred at that temperature for 30 minutes. The mixture was washed successively with water and brine, dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 20-50% ethyl acetate in hexanes to give the title compound as a colorless oil (3.25 g, 84%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 9.62 (s, 1 H), 7.18-7.41 (m, 5 H), 4.37-4.56 (m, 3 H), 4.08-4.14 (m, 1 H), 3.88-3.74 (m, 1 H), 3.56 (dd, J=11.7, 4.7 Hz, 1 H) 2.19-2.29 (m, 1 H) 1.95-2.05 (m, 1 H) 1.45 (s, 9 H).
Reaction SMILES: OO.[C:3]1([CH3:13])[CH:8]=[CH:7][C:6](S(O)(=O)=O)=[CH:5][CH:4]=1.[C:14](OC)(=O)[C:15](C)=C.[CH3:21]OC1C=CC(O)=CC=1>>[CH2:14]1[CH:4]2[CH:5]3[CH:6]=[CH:7][CH:8]([CH:3]2[CH:13]=[CH:15]1)[CH2:21]3
Reactant: C=C(C)C(=O)OC
Reactant: COc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: OO
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Into the same apparatus as in Example 9 were charged 194 g (1 mole) of ethylene glycol monodicyclopentenyl ether ##STR16## peroxide content: 35 ppm in terms of H2O2), and 5 g of p-toluenesulfonic acid. The temperature was raised to 60° C. with stirring and kept there for 10 minutes. Then, 350 g of methyl methacrylate and 0.13 g of 4-methoxyphenol were charged into the apparatus, and thereafter the reaction was carried out in the same manner as in Example 1. One hour after the beginning of raction, the reaction solution was colored dark-brown so seriously that when it was placed in a 18 mm diameter test tube, a substance on one side of the test tube could not be seen through the test tube from the other side. At that time the conversion was 25%. In addition, oligomer by-products having a molecular weight of about 700 to 1000 (which were presumed to be oligomers formed by ionic polymerization of dicyclopentadiene) had been formed in an amount of about 2%.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][CH:16]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[C:40](=[O:41])[NH:39][N:38]=[CH:37]2)[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[F:23][CH:22]([F:24])[O:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:39]2[C:40](=[O:41])[N:36]([C:28]3[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=3)[CH:37]=[N:38]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: FC(F)Oc1ccc(CBr)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(OC(F)F)cc3)c2=O)nc1C
Yield: 79 %

Procedure:
Following the procedure as described in Example 19, making variation as required to replace 4-(trifluoromethyl)benzyl bromide with 1-(bromomethyl)-4-(difluoromethoxy)benzene to react with ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate, the title compound was obtained as a white solid in 79% yield:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[CH2:8]2.N1CCCC1.O.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:13])[CH:8]2[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: COc1cccc2c1CCC(=O)C2
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCNC1
Product: CCOC(=O)CC1C(=O)CCc2c(OC)cccc21
Yield: 43.8 %

Procedure:
28 g (0.16 mol) of 5-methoxy-2-tetralone and 12.5 g (14.5 ml, 0.175 mol) of pyrrolidine were dissolved in 150 ml of toluene. The mixture was boiled on a water separator for 2 hours, cooled, treated with 31.7 g (0.19 mol) of ethyl bromoacetate and boiled under reflux for 2 hours. The mixture was then concentrated, dissolved in 150 ml of ethanol/water (5:1) and again boiled under reflux for 2 hours. The solvent was distilled off in a vacuum and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated sodium chloride solution, dried with MgSO4, filtered and concentrated. The residue was dissolved in ether, treated with active charcoal and recrystallized. There were obtained 18.4 g of ethyl rac-1,2,3,4-tetrahydro-5-methoxy-2-oxo-1-napthylacetate as white crystals. A further 10.3 g of white crystals could be obtained from the mother liquors by chromatography over silica gel with cyclohexane/ethyl acetate (4:1). Total yield: 28.7 g (68%) of white crystals with m.p. 36°-40°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[O-:12][Mn](=O)(=O)=O.[K+].[OH2:18]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([OH:12])=[O:18]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: O
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Temperature: 60 °C

Procedure:
2-Bromo-4-nitrotoluene (5.0 g, 23.14 mmol) was dissolved in pyridine (23 mL) and water (46 mL). The heterogeneous mixture was heated to 60° C. and KMnO4 (18.29 g, 115.7 mmol) was added carefully. The mixture was then heated under reflux overnight. The reaction mixture was filtered and washed with boiling water. The solution was then made acidic and extracted into ethyl acetate, dried over Na2SO4 and the solvent was removed in vacuo. The crude product was dissolved in aqueous NaOH and washed with hexanes. The aqueous phase was made acidic and the product was extracted into ethyl acetate. The ethyl acetate solutions were combined and dried over Na2SO4 and the solvent was removed in vacuo to provide the desired product (3.72 g): m.p. 158-160° C.; 1H NMR (CD3OD) d 7.81 (1H, d, J=8.5 Hz), 8.08 (1H, d, J=8.5 Hz), 8.30 (1H, s); 13C NMR (CD3OD) d 121.96, 122.75, 129.36, 132.24, 139.52, 149.54, 167.75; Anal. Calc. for C7H4BrNO4 *0.1 ethyl acetate, C: 34.88, H: 1.90, N: 5.50; Found, C: 34.68, H: 1.86, N: 5.82.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[O:8])[CH2:33][CH2:32]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccccc2N2CCNCC2)cc1
Reactant: O=C(CCCCCBr)NCc1ccncc1
Product: COc1ccc(-c2ccccc2N2CCN(CCCCCC(=O)NCc3ccncc3)CC2)cc1

Procedure:
The title compound was prepared starting from 6-bromo-N-(4-pyridylmethyl)hexa namide and 1-[2-(4-methoxyphenyl)phenyl]piperazine following the procedure outlined for Example 21. 1H NMR (CDCl3): δ 1.34-1.43 (m, 2H), 1.53-1.63 (m, 2H), 1.67-1.77 (m, 2H), 2.28 (t, 2H, J=7.4 Hz), 2.42 (app. t, 2H), 2.66 (br s, 4H), 3.10 (br s, 4H),3.81 (s, 3H), 4.45 (d, 2H, J=6.1 Hz), 6.10 (br t, 1H, D2O exchanged), 6.94 (d, 2H, J=8.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.09-7.16 (m, 3H), 7.22-7.30 (m, 2H), 7.46 (d, 2H, J=8.8 Hz), 8.55 (dd, 2H, J=1.4, 4.4 Hz). GC-MS m/z 473 (M+1, 1), 472 (M+, 5), 379 (15), 282 (82), 226 (100), 210 (43).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[CH:13][C:14]#[N:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[Cl:19][C:20]1[CH:25]=[C:24]([N:26]=C=O)[CH:23]=[C:22]([Cl:29])[CH:21]=1.[CH2:30]([N:32]1[C:44]2[CH:43]=[CH:42][C:41]([NH2:45])=[CH:40][C:39]=2[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH3:31]>>[C:14]([CH:13]=[C:11]1[CH2:12][N:8]([C:6]([NH:26][C:24]2[CH:25]=[C:20]([Cl:19])[CH:21]=[C:22]([Cl:29])[CH:23]=2)=[O:7])[C@H:9]([C:16]([NH:45][C:41]2[CH:42]=[CH:43][C:44]3[N:32]([CH2:30][CH3:31])[C:33]4[C:38]([C:39]=3[CH:40]=2)=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:18])[CH2:10]1)#[N:15]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C[C@H]1C(=O)O
Product: CCn1c2ccccc2c2cc(NC(=O)[C@@H]3CC(=CC#N)CN3C(=O)Nc3cc(Cl)cc(Cl)c3)ccc21

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(cyanomethylene)-2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 60% purity by LC/MS. MS(ESI+): m/z=532.8.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1>C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([O:14][CH3:15])[C:9]([O:12][CH3:13])=[CH:10][C:11]=1[N+:1]([O-:4])=[O:2]
Reactant: COc1ccc(Br)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc(Br)c([N+](=O)[O-])cc1OC
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of concentrated nitric acid (14 mL) and acetic acid (42 mL) was cooled to 110° C. while stirring, and then 4-bromo-1,2-dimethoxybenzene (2 g, 9.21 mmol) was gradually added to the stirred mixture. The reaction mixture was warmed to 15° C., and stirring was continued for 60 minutes. The reaction mixture was cooled to 0° C. and stirred while adding ice water, and then extraction was performed with ether. The obtained organic layer was neutralized with saturated aqueous solution of sodium hydrogencarbonate and potassium carbonate, and then washed with water. After drying the organic layer over anhydrous magnesium sulfate, the desiccant was filtered off and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized from ethanol to give 2.09 g of the title compound as light yellow crystals.
Reaction SMILES: [C:1]([CH:8]([C@H:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[CH:16]=1)[CH2:13][NH2:14])C(O)=O)(OC(C)(C)C)=[O:2].B.O1CCCC1>O1CCCC1>[ClH:21].[NH2:14][CH2:13][C@@H:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]2[CH:23]=[C:24]([C:28]#[N:29])[CH:25]=[CH:26][CH:27]=2)[CH:16]=1)[CH2:8][CH2:1][OH:2]
Reactant: CC(C)(C)OC(=O)C(C(=O)O)[C@@H](CN)c1ccc(Cl)c(-c2cccc(C#N)c2)c1
Agent: B
Solvent: C1CCOC1
Product: Cl
Product: N#Cc1cccc(-c2cc([C@H](CN)CCO)ccc2Cl)c1
Temperature: 0 °C
Reaction time: 72 h
Yield: 5.3 %

Procedure:
Two-hundred (200) mg (0.48 mmol) of Boc-(3R)-4-amino-3-[4-chloro-3-(3-cyanophenyl)phenyl]butanoic acid (52a) (200 mg, 0.48 mmol) was dissolved in 1 mL of tetrahydrofuran (THF). The reaction mixture was cooled to 0° C. and 3 equivalents of 2M borane/THF solution was added. The mixture was warmed to room temperature and stirred for 3 days. The reaction mixture was then carefully quenched with excess methanol. After stirring for 15 min, 2 mL of 1N NaOH was added and the mixture stirred for one hour. The mixture was extracted with ethyl acetate (3×10 mL), the aqueous solution acidified to pH 3, and then extracted two additional times with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by HPLC to provide the title compound (53) (4.3 mg, 10% yield). 1H-NMR (400 MHz, CD3OD): δ 1.93-2.01 (m, 1H), 1.81-1.88 (m, 1H), 3.22-3.27 (dd, J=22.4, 9.6 Hz, 1H), 3.14-3.19 (m, 1H), 3.30-3.39 (m, 1H), 3.52-3.57 (m, 1H), 7.54-7.56 (m, 1H), 7.33-7.36 (m, 2H), 7.61-7.65 (m, 1H), 7.75-7.78 (m, 1H), 7.80-7.81 (m, 1H); MS (ESI) m/z 301.04 (M+H)+.
Reaction SMILES: [CH2:1]([O:10][N:11]=[C:12]([CH3:16])[C:13](O)=[O:14])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:19])=O.N.C(ON=C(C)C(N)=O)C=CC1C=CC=CC=1>O.C(Cl)(Cl)Cl>[CH2:1]([O:10][N:11]=[C:12]([CH3:16])[C:13]([Cl:19])=[O:14])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CC(=NOCC=Cc1ccccc1)C(=O)O
Agent: CC(=NOCC=Cc1ccccc1)C(N)=O
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=NOCC=Cc1ccccc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(Cinnamyloxyimino)-propionyl chloride is prepared from 4.38 g. (20 mmol) 2-(cinnamyloxyimino)-propionic acid and 3.57 g. (30 mmol) thionyl chloride in the manner described in Example 6. The crude acid chloride is dissolved in 20 ml. chloroform and added, while stirring, to an ice-cooled solution of ammonia in 40 ml. chloroform. The reaction mixture is left to stand overnight at ambient temperature and then shaken up with 100 ml. water. Subsequently, the organic phase is first washed with 0.5 N hydrochloric acid, then with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous sodium sulphate and evaporated in a vacuum. The residue is recrystallized from a mixture of ethyl acetate and ligroin to give 2.9 g. (66% of theory) 2-(cinnamyloxyimino)-propionamide; m.p. 120°-121° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:15]1(C)[C:19]2(CS(O)(=O)=O)[C:20](C[CH:16]1[CH2:17]C2)=[O:21]>O1C=CCCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH:20]2[CH2:19][CH2:15][CH2:16][CH2:17][O:21]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: O[C@@H]1CCN(Cc2ccccc2)C1
Agent: C1=COCCC1
Product: c1ccc(CN2CC[C@@H](OC3CCCCO3)C2)cc1
Reaction time: 14 h
Yield: 120 %

Procedure:
To a stirred solution of (R)-(+)-1-benzyl-3-pyrrolidinol (5.00 g, 28 mmol) and D-camphor-10-sulfonic acid (6.97 g, 30 mmol) in CH2Cl2 (10 ml) was added 3,4-dihydro-2H-pyran (20 ml) at rt and the reaction mixture was stirred for 14 h (in most cases, the reaction was completed after exothermic reaction subsided). The reaction mixture was diluted with CH2Cl2 (100 ml), washed with saturated NaHCO3 aqueous solution, dried (Na2SO4), and concentrated to give brown oil. This was purified by column chromatography (silica gel: 200 g, CH2Cl2 /MeOH: 40/1 as eluent) to give 8.78 g (97.6%) of desired compound as brown oil.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH:3]=1.C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:21])=[O:10])[CH2:4][CH:3]=1
Reactant: CC1=CC[C@@H](C(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1=CC[C@@H](C(=O)Cl)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
(1S)-4-Methyl-cyclohex-3-ene-1-carboxylic acid (250 mg, 1.78 mmol), azeotropically dried by evaporation from toluene was dissolved in dichloromethane (4 mL) and treated with dimethylformamide (1 drop). The reaction mixture was cooled to 0° C. and treated dropwise with oxalyl chloride (0.42 mL, 4.5 mmol). The reaction mixture was allowed to warm to ambient temperature while stirring for 4 h. The solution was concentrated, treated with hexanes and concentrated again to afford (1S)-4-methyl-cyclohex-3-ene-1-carboxylic acid chloride as a light yellow oil which was used immediately in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH3:13])=[O:11].Cl[CH2:35]Cl>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:14][C:10]([O:12][CH2:13][CH3:35])=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(Br)cc1
Reactant: ClCCl
Product: CCOC(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Bromobenzaldehyde (9.25 g) was dissolved in dry dichloromethane (250 ml) at 25° C. under nitrogen. Carbomethoxymethylene triphenylphosphorane (17.4 g) (ex Lancaster) was added and the solution stirred at 25° C. for 18 hours. The solvent was removed under vacuum. The residue was washed with hexane and filtered. Removal of the hexane under vacuum gave ethyl 4-bromocinnamate (12.12 g). NMR 1H; 7.35 (5H,m), 6.38 (1H,d), 4.1(2H,q), 1.35(3H,t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:10].[OH-].[K+].[F:13][C:14]([F:21])([F:20])[C:15]([F:19])=[C:16]([F:18])[F:17].NC1C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][C:16]([F:18])([F:17])[CH:15]([F:19])[C:14]([F:21])([F:20])[F:13])[NH2:8].[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][C:16]([F:17])=[C:15]([F:19])[C:14]([F:21])([F:20])[F:13])[NH2:8]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: Nc1cc(Cl)c(OC(F)(F)C(F)C(F)(F)F)c(Cl)c1
Product: Nc1cc(Cl)c(OC(F)=C(F)C(F)(F)F)c(Cl)c1
Reaction time: 0.42 h

Procedure:
To 1.1 liters of tetrahydrofuran containing 44.5 g of 2,6-dichloro-4-aminophenol and 3.2 g potassium hydroxide, was added subsurface 38.7 g of hexafluoropropene. The addition was complete in 25 minutes at a temperature of 8°-11° C. Analysis by liquid chromatography indicates no starting aniline present. Most of the THF was removed under vacuum, 500 mL water was added and the resulting mixture was extracted 3×500 mL ethyl ether. The combined extracts were washed with 2×100 mL 1N NaOH, 2×200 mL brine, dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to give a mixture. This mixture was separated by prep LC to give 46.8 g of 3,5-dichloro-4-(1,1,2,3,3,3-hexafluoropropoxy)aniline and ~4 g of 3,5-dichloro-4-(1 ,2,3,3,3-pentafluoropropenoxy) aniline . Proton and 19F nmr and mass spectra were consistent with the proposed structures.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9](Cl)[CH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+]>>[OH:11][CH2:10][CH2:9][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1cccc(Cl)c1
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: OCCNc1cccc(Cl)c1

Procedure:
A mixture consisting of 50.8 gm of 3-chloro-aniline, 36 gm of ethylenechlorohydrin and 50 gm of anhydrous sodium carbonate was refluxed for four hours, while stirring. Thereafter, the reaction mixture was suction-filtered while still hot, and the filter cake was washed with ethyl acetate. The filtrate was then distilled in vacuo; the desired product passed over at 182° C./14 mm Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7](=[O:10])[NH:8][CH:9]=1)([O-:3])=[O:2].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>N1C=CC=CC=1.O1CCOCC1.N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:8]2[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]2=[O:10])=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COC(=O)c1cc([N+](=O)[O-])cn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 52.3 %

Procedure:
A mixture of methyl 5-nitro-2-oxo-1,2-dihydropyridine-3-carboxylate (850 mg, 4.29 mmol), 4-fluorophenylboronic acid (1.40 g, 10 mmol, Combi-Blocks) and copper acetate (200 mg, 1.1 mmol) in pyridine (1 mL) and dioxane (20 mL) was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with a solution of ammonia. The solid was collected, washed with water and dried to afford the title compound (656 mg, 52%). 1H NMR (DMSO-d6) δ 8.95 (d, 1H, J=3.2 Hz), 8.80 (d, 1H, J=3.2 Hz), 7.40 (m, 2H), 7.25 (m, 2H), 3.95 (s, 3H); MS(ESI+) m/z 293 (M+H)+.
Reaction SMILES: CC1C=CC(N2C3C(=CC=CC=3)C=C2)=CC=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.I[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1>>[CH3:53][O:52][C:49]1[CH:50]=[CH:51][C:46]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([CH2:26][N:27]4[CH2:32][CH2:31][CH:30]([C:33]5[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:42])[CH3:43])[CH:36]=[CH:37][CH:38]=5)[CH2:29][CH2:28]4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[CH:47][CH:48]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: COc1ccc(I)cc1
Agent: Cc1ccc(-n2ccc3ccccc32)cc1
Product: COc1ccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)cc1
Yield: 56.1 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-iodo-4-methoxybenzene (46.8 mg, 0.200 mmol) gave the desired product (27 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.70–6.58 (m, 14H), 3.88 (s, 3H), 3.67 (s, 2H), 3.14–3.01 (m, 2H), 2.57–2.41 (m, 2H), 2.25–2.01 (m, 2H), 1.93–1.69 (m, 4H), 1.24 (d, 6H, J=7.2 Hz); ESMS m/e: 482.2 (M+H)+.