Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:11]([CH2:19]P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[C:44]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O1CCCC1>[CH2:2]([O:9][C:10]1[C:11]([CH:19]=[C:44]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COc2cc3c(cc2C[PH](c2ccccc2)(c2ccccc2)c2ccccc2)OCC3)cc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=C(c1ccccc1)c1ccccc1)c1cc2c(cc1OCc1ccccc1)CCO2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 22.2 %

Procedure:
A mixture of (5-benzyloxy-2,3-dihydro-benzofuran-6-yl)methyl triphenylphosphine iodide (2.0 g, 0.0033 mol) in tetrahydrofuran (20 ml) was cooled to an internal temperature of 5° C. under nitrogen and a solution of n-butyllithium (1.55M in hexane, 1.9 ml, 0.0030 mol) was added dropwise. The resulting mixture was stirred for 10 minutes then benzophenone (0.47 g, 0.0030 mol) was added portionwise. The ice bath was removed and the reaction was allowed to stir for 18 hours, then heated to reflux for 4 hours. The reaction mixture was concentrated to a dark oil which was dissolved in ethyl acetate (20 ml), washed with water (10 ml), saturated sodium chloride (10 ml). The combined organic layers were dried (MgSO4), concentrated then chromatographed over silica gel (hexane/ethyl acetate, 90/10, an eluent) to afford 1-(5-benzyloxy-2,3-dihydrobenzofuran-6-yl)-2,2-diphenyl-ethene (0.27 g, 22%).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][NH:24]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=3[S:10][C:11]=2[CH:12]([NH:14][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1sc2ccccc2c1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1sc2ccccc2c1-c1ccccc1
Temperature: 120 °C
Reaction time: 72 h

Procedure:
A mixture of 1-(3-phenylbenzo[b]thiophen-2-yl)ethylamine from Example 23 (160 mg, 0.63 mmol), 6-chloro-9H-purine (98 mg, 0.63 mmol) and DIPEA (0.16 mL, 0.95 mmol) in n-butanol (1.3 mL) was stirred in a sealed vial for 3 days at 120° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-6% MeOH in DCM) and then triturated with EtOAc affording 101 (105 mg, 45%). LCMS: RT 4.33 min [M+H]+ 372.1. 1H NMR (DMSO, 400 MHz): δ 8.21 (1H, s), 8.16-8.10 (2H, m), 7.92-7.86 (1H, m), 7.66-7.54 (4H, m), 7.50-7.44 (1H, m), 7.37-7.26 (3H, m), 5.76 (1H, s), 1.50 (3H, d, J=6.94 Hz)
Reaction SMILES: [CH2:1]([C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](=O)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(NCC)C>C(O)C>[C:11]1([C:10]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][CH:17]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[OH:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:11]1([C:10]2[C:8](=[O:9])[CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:17][CH2:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: O=CC=Cc1ccccc1
Solvent: CCNCC
Solvent: CCO
Product: O=C1C(c2ccccc2)=C(c2ccccc2)CCC1c1ccccc1
Product: Oc1c(-c2ccccc2)ccc(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.33 h
Yield: 91 %

Procedure:
2,3,6-Triphenylphenol was prepared according to A. S. Hay and R. F. Clark (Macromolecules, 3, 533, 1970). 11.36 g (54 mmoles) of dibenzylketone, 7.14 g (54 mmoles) of cinnamaldehyde and 5 mL of diethylamine were mixed and the solution became yellow and after 20 min. a yellow solid deposited. The solid was added to ethanol (80 mL), cooled and filtered to yield 2,3,6-triphenylcyclohexenone (91%). The product (8.0 g) was mixed with 1 g of 5% Pd on carbon and heated at 270° C. for 30 min and then cooled. The mixture was dissolved in hot ethylacetate and the hot solution was filtered and cooled to yield 2,3,6-triphenylphenol (69%). The oxidation of triphenylphenol (5 g) was carried out in butyronitrile (50 mL) with a CuCl catalyst (0.4 g) by passing oxygen through the stirred solution at 100° C. for 8 hours. The reaction mixture was cooled and filtered to yield (82%) of the crude biphenol. Reduction with a few drops of hydrazine in hot acetic acid reduced any of the diphenoquinone in the product to give 2,2',3,3',5,5'-hexaphenyl-[1,1'-biphenyl]-4,4'-diol which was further purified by crystallization.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[NH:16][C:17]4[C:18]([N:31]=2)=[C:19]2[C:24](=[C:25]5[C:30]=4[CH:29]=[CH:28][CH:27]=[N:26]5)[N:23]=[CH:22][CH:21]=[CH:20]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:35].CO>CN(C)C=O>[CH3:35][N:31]1[C:18]2[C:17](=[C:30]3[C:25](=[C:24]4[C:19]=2[CH:20]=[CH:21][CH:22]=[N:23]4)[N:26]=[CH:27][CH:28]=[CH:29]3)[N:16]=[C:15]1[C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2
Reactant: CI
Reactant: c1ccc2c(-c3nc4c5cccnc5c5ncccc5c4[nH]3)c3ccccc3cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1c(-c2c3ccccc3cc3ccccc23)nc2c3cccnc3c3ncccc3c21
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture of the 2-(9-anthryl)imidazo[4,5-f]-[1,10]phenanthroline (10 grams) and sodium hydride (11.5 grams) in 300 milliliters of dimethylformamide was stirred at ambient temperature (about 23° C.) for 30 minutes. Into the resulting mixture was added 18.7 grams of iodomethane. The reaction was stirred overnight at room temperature when 100 milliliters of methanol was added. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven to give the crude product which was further purified by sublimation. The product and its structure was confirmed by proton NMR analysis.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([O:7][CH:8]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH3:9])=[CH:5][CH:4]=1)#[N:2].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>ClCCl.O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([C:14]([NH:42][CH2:43][C:44]3[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=3[CH3:50])=[O:16])=[CH:17][CH:18]=2)[CH3:9])=[CH:19][CH:20]=1)#[N:2]
Reactant: CC(Oc1ccc(C#N)cc1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccc(C#N)cc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.4 %

Procedure:
A mixture of 4-(1-(4-cyanophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (382 mg, 2 mmol), 1-Hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.4 mL) in dichloromethane (55 mL) were stirred at 25° C. for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added to the above mixture. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (10 mL) was added and the mixture was extracted with dichloromethane (50 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was evaporated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(4-cyanophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (150 mg, 48%) as a white solid. LRMS (M+H+) m/z: cald. 401.17. found 401.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[O:15][N:14]=[C:13]([CH2:16][O:17]C4CCNCC4)[N:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][N:3]=1.Br[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.[CH2:31]1[CH2:41][CH2:40][N:39]2C(=NC[CH2:37][CH2:38]2)CC1>O1CCOCC1>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[O:15][N:14]=[C:13]([CH:16]([O:17][N:39]4[CH2:38][CH2:37][CH2:31][CH2:41][CH2:40]4)[C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[N:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Clc1nccc2oc(-c3nc(COC4CCNCC4)no3)cc12
Reactant: Brc1ncccn1
Solvent: C1COCCO1
Product: Clc1nccc2oc(-c3nc(C(ON4CCCCC4)c4ncccn4)no3)cc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A stirred solution of 4-[5-(4-chlorofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester (Example 57, 150 mg, 346 μmol) in CH2Cl2 (4 mL) was treated with H2O (6 μL) and TFA (1.5 mL). After 1 h, the reaction was concentrated in vacuo, then the excess TFA was removed through azeotropic distillation with PhMe under reduced pressure. The remainder was partitioned between EtOAc and 2M NaOH. The aqueous phase was extracted further with EtOAc, then the combined EtOAc extracts were washed with brine and dried (MgSO4). Filtration and solvent evaporation furnished 4-chloro-2-[3-(piperidin-4-yloxymethyl)-[1,2,4]oxadiazol-5-yl]furo[3,2-c]pyridine: m/z (ES+)=335.1 [M+H]+. A mixture of this amine (105 mg, 315 μmol), 2-bromopyrimidine (55 mg, 346 μmol) and DBU (95 μL, 630 μmol) in dioxane (2 mL) was stirred at ambient temperature for 16 h. The reaction was concentrated and the residue purified by column chromatography (EtOAc-IH, 3:7) to yield the title compound: RT=3.40 min; m/z (ES+)=413.1 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:8])[C:4]([O:6][CH3:7])=[O:5].C([O-])([O-])=O.[K+].[K+].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]([CH2:2][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[CH2:8]
Reactant: C1COCCN1
Reactant: C=C(CBr)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CN1CCOCC1)C(=O)OC
Reaction time: 8 h

Procedure:
To a mixture of methyl 2-(bromomethyl)acrylate (119 μl, 1 mmol) and K2CO3 (138 mg, 1 eq) in acetonitrile (2 ml) was added morpholine (96 μl, 1.1 mmols). The mixture was stirred overnight, filtered and concentrated. The residue was partitioned between ether and water, and organic layer was isolated, washed with brine and dried (MgSO4). Solvent was removed and residue was purified by column chromatography. Ethyl acetate eluted out the title compound as clear oil (110 mg, 59%).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[S:2].[CH3:13][C:14]([C:17]1[CH:18]=[C:19]([C:34]([NH:36][NH2:37])=[NH:35])[CH:20]=[C:21]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])([CH3:16])[CH3:15].C(N(CC)CC)C>O1CCCC1>[CH3:32][C:30]([C:21]1[CH:20]=[C:19]([C:34]2[N:36]=[N:37][C:1](=[S:2])[N:35]=2)[CH:18]=[C:17]([C:14]([CH3:13])([CH3:15])[CH3:16])[C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])([CH3:31])[CH3:33]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCOCOc1c(C(C)(C)C)cc(C(=N)NN)cc1C(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCOCOc1c(C(C)(C)C)cc(C2=NC(=S)N=N2)cc1C(C)(C)C

Procedure:
1,1'-Thiocarbonyldiimidazole (0.64 g, 0.0036 mole) is added portionwise to a stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzene carboximidic acid hydrazide (1.0 g, 0.0028 mole) and triethylamine (0.43 ml, 0.003 mole) in tetrahydrofuran (5.0 ml). After the addition is complete the mixture is heated to reflux for 1.5 hours. The solution is cooled and concentrated in vacuo. The residue is dissolved in ether (20 ml) and the solution washed with aqueous 2M HCl, saturated aqueous NaHCO3, saturated aqueous NaCl, and dried over MgSO4. Filtration and concentration in vacuo gives 0.94 g (1.1 g theor., 86%) product after recrystallization from ethyl acetate/isopropyl ether, mp 187° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C(N(CC)CC)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[NH:22][C:21]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:32]=3[O:41][CH2:42][CH3:43])=[N:20]2)=[CH:15][CH:14]=1.[OH:44][CH2:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]2[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[N:22]([C:1]([N:49]3[CH2:50][CH2:51][CH:46]([CH2:45][OH:44])[CH2:47][CH2:48]3)=[O:2])[C:21]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][C:32]=3[O:41][CH2:42][CH3:43])=[N:20]2)=[CH:17][CH:18]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Reactant: OCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
Phosgene (1.8 mL, 3.6 mmol, 1.9 M in toluene) was added dropwise to a cooled (0° C.) solution of triethylamine (0.57 mL, 4.0 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluro-phenyl)-4,5-dihydro-1H-imidazole (550 mg, 1.2 mmol, example 1) in methylene chloride (5.0 mL). The reaction mixture was stirred for 0.5 h at 0° C. The solvent was removed under reduced pressure. The residue was kept under high vacuum for 30 min and dissolved in methylene chloride (5.0 mL). Triethylamine (0.170, 1.2 mmol) and 4-(hydroxymethyl)piperidine (0.50 g, 4.4 mmol) were added. After 1 h, the reaction was worked up with aqueous sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine and dried over anhydrous sodium sulfate. Evaporation of the solvents and flash chromatography of the residue over silica gel using 1-4% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-hydroxymethyl-piperidin-1-yl]-methanone (560 mg, 79%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#N.[OH-:11].[Na+].Cl.[OH2:14]>>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]([OH:14])=[O:11]
Reactant: N#Cc1ccc(O)cc1F
Reactant: O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(O)cc1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile (20.00 g, 145.9 mmol) in 160 mL of water, was added 50% aqueous sodium hydroxide (40.00 g, 500.0 mmol). The mixture was heated to reflux for 4 hours, cooled to room temperature, poured into iced concentrated hydrochloric acid, and extracted with ether. The product was extracted into saturated aqueous sodium bicarbonate and the ether layer discarded. This aqueous extract was acidified with concentrated hydrochloric acid and extracted with ether. The organic extract was dried over magnesium sulfate, filtered, and evaporated to give a white solid (22.90 g) of 2-fluoro-4-hydroxybenzoic acid in 100% yield, 1H NMR (300 MHz, CD3COCD3) δ (ppm): 9.80 (b, 1H), 7.87 (t, 1H), 6.77 (dd, 1H), 6.66 (dd, 1H). 19F-NMR (300 MHz, CD3COCD3) δ (ppm): −108.13 (s, decoupled). 2-Fluoro-4-hydroxybenzonitrile: 1H NMR (300 MHz, CD3COCD3) δ (ppm): 7.61 (t, 1H), 6.81 (m, 2H), 5.80 (b, 1H). 19F-NMR (300 MHz, CD3COCD3) δ (ppm): 108.82 (s, decoupled)
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH2:12]([C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[N:23]=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH2:12]([C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[N+:23]([O-:6])=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][CH2:14][CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCc1c2c(nc3c1CCCC3)CCCC2
Solvent: ClCCl
Product: CCCCc1c2c([n+]([O-])c3c1CCCC3)CCCC2
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Into a 1 L round-bottomed flask equipped with a magnetic stirrer, a reflux condenser and a 250 ml addition funnel are placed 56.3 g (0.26 mol) of m-chloroperoxybenzoic acid (Note 12) and 350 mL of methylene chloride. The resulting suspension is stirred as a solution of 38.0 g (0.16 mol) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine in 120 mL of methylene chloride is added rapidly. When the reaction mixture ceases to boil gently from the heat of reaction, the reaction flask is warmed to extend the reflux period to a total of 2.5 hrs. (Note 10). The reaction mixture is cooled to room temperature, extracted with 0.5M aqueous sodium hydroxide (4×450 mL), dried using anhydrous sodium sulfate and concentrated under reduced pressure using a rotary evaporator. Residual solvent is removed at 0.1 mm, yielding 40 g (99%) of 9-n-butyl-1,2,3,4,5,6,7,8-octahydroacridine-N-oxide as a yellow crystalline solid, mp 96°-100° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])[C:3]=1[C:14]#[N:15].[CH3:16][N:17]=[C:18]=[O:19].O>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:16][NH:17][C:18]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]([CH2:11][CH2:12][CH3:13])[CH2:8][CH2:9][CH3:10])[C:3]=1[C:14]#[N:15])=[O:19]
Reactant: CN=C=O
Reactant: CCCN(CCC)c1nsc(N)c1C#N
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)c1nsc(NC(=O)NC)c1C#N
Yield: 70.6 %

Procedure:
A solution of 7.0 g of 5-amino-4-cyano-3-(dipropylamino)isothiazole, 3.6 g of methyl isocyanate and 40 drops of dibutyltin diacetate in 50 ml of tetrahydrofuran was heated under reflux overnight. Thin-layer chromatographic analysis indicated the reaction to be complete. The reaction mixture was poured into rapidly stirred, cold water. The solid precipitate was collected by filtration. The filtrate was extracted with methylene chloride. The solid was combined with the extract and the mixture dried over calcium chloride, then filtered through magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue was taken up in a mixture of toluene and benzene to which a little ethanol had been added. Pentane was then added to promote crystallization. The recrystallization yielded 6.2 g of 1-methyl-3-(4-cyano-3-(dipropylamino)-5-isothiazolyl)urea, m.p. 179°-180°. The nmr and ir spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].[H-].[Na+].[C:20](Cl)(=[O:22])[CH3:21].[O:24]1CC[CH2:26][CH2:25]1>>[C:20]([N:9]1[C:10]2[C:11](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:7]([CH2:6][CH2:5][NH:4][C:2](=[O:3])[CH3:1])=[CH:8]1)(=[O:22])[CH3:21].[C:20]([N:9]1[C:10]2[C:11](=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:7]([CH2:6][CH2:5][N:4]([C:25]([CH3:26])=[O:24])[C:2](=[O:3])[CH3:1])=[CH:8]1)(=[O:22])[CH3:21]
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Reactant: C1CCOC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(c1)c(CCN(C(C)=O)C(C)=O)cn2C(C)=O
Product: COc1ccc2c(c1)c(CCNC(C)=O)cn2C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Melatonin (126 mg) is dissolved in tetrahydrofuran (10 ml) in a 50 ml round-bottomed flask, sodium hydride (200 mg) is then added and the mixture is maintained at reflux (10 min). After cooling (0° C.), acetyl chloride is added and the mixture is kept stirring overnight (room temperature). After filtration and dilution (EtOAc), the organic phase is washed with water and then separated on a silica plate. N-[2-(1-Acetyl-5-methoxyindol-3-yl)ethyl]acetamide (1) is mainly obtained, along with a side product, N-[2-(1-acetyl-5-methoxyindol-3-yl)ethyl]diacetamide (10) (cf. Example 10).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>CO>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[O:30][CH3:31])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A suspension of (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate (86.95 g, 174 mmol) in 350 mL MeOH was heated to 70° C., was treated with sodium methoxide 25% wt in MeOH (19.06 ml, 69.8 mmol) and was allowed to stir overnight. The reaction mixture was then concentrated. The crude solid was triturated with IPA yielding 47.13 g clean product. The IPA washings were concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave an additional 10.76 g of slightly impure product. 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (57.89 g, 128 mmol, 73.4% yield). m/z (ESI) 451.8 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][NH:18][C:17](=[O:20])[NH:16][CH2:15]2)=[CH:10][C:9]=1Br)(C)(C)C.[C:23]1(B(O)O)[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:15][NH:16][C:17](=[O:20])[NH:18][CH2:19]2)=[CH:10][C:9]=1[C:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=1
Reactant: OB(O)C1=CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CNC(=O)NC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CNC(=O)NC2)cc1C1=CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[2-Bromo-4-(2-oxo-hexahydro-pyrimidin-5-yl)-phenyl]-carbamic acid tert-butyl ester (99 mg, 0.26 mmol, as prepared in the previous step) was dissolved in TFA (1 mL). The resulting mixture was stirred at RT for 30 min and concentrated in vacuo. The residue obtained was dried in vacuo for 1 h and dissolved in EtOH (0.5 mL) and toluene (1 mL). To this solution cyclohex-1-enyl boronic acid (20.5 mg, 0.16 mmol), 2M Na2CO3 (0.5 mL, 1 mmol) and Pd (PPh3)4 (30 mg, 0.025 mmol) were added. The resulting mixture was heated at 80° C. overnight. The reaction mixture was allowed to cool to RT and extracted with EtOAc (2×10 mL). The EtOAc layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was purified on silica (2% MeOH-EtOAc) to afford the title compound (31 mg) contaminated with Ph3PO, which was used in the next step without further purification: Mass spectrum (ESI, m/z): Calcd. for C16H21N3O, 272.1 (M+H). found 272.1.