Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[Cl:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[Cl:27])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Clc1cccc(CBr)c1Cl
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 90 °C
Reaction time: 4 h
Yield: 82.2 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.8 g, 2.70 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-2,3-dichlorobenzene (0.778 g, 3.24 mmol) and potassium carbonate (1.120 g, 8.10 mmol). The resulting reaction mixture was stirred at 90° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (1.01 g, 82%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.55 (s, 3H) 3.03-3.18 (m, 4H) 3.79-3.89 (m, 4H) 5.35 (s, 2H) 6.31 (dd, J=7.83, 1.26 Hz, 1H) 6.54 (d, J=2.02 Hz, 1H) 7.08 (t, J=7.96 Hz, 1H) 7.17 (d, J=2.02 Hz, 1H) 7.45 (dd, J=8.06, 1.55 Hz, 1H); MS (ES+) m/e 453.8 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:9][CH2:10][CH3:11])[C:5](=[NH:8])OC)[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][NH2:20])[CH:16]=[CH:17][CH:18]=1>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][NH:20][C:5](=[NH:8])[CH:4]([O:3][CH2:1][CH3:2])[O:9][CH2:10][CH3:11]
Reactant: NCc1cccc(Cl)c1
Reactant: CCOC(OCC)C(=N)OC
Solvent: CO
Product: CCOC(OCC)C(=N)NCc1cccc(Cl)c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
In a nitrogen-flushed sealed tube was placed methyl 2,2-diethoxyacetimidate (2 g, 12.41 mmol) in methanol (6 mL) and (3-chlorophenyl)methanamine (1.444 mL, 11.82 mmol). The tube was capped and heated to 70° C. After 18 hours, the reaction was cooled to room temperature and the reaction was concentrated to yield N-(3-chlorobenzyl)-2,2-diethoxyacetimidamidea (2.3 grams, 8.5 mmol, 71%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:20]=2)=[CH:13][C:12]2[C:7](=[CH:8][C:9]([F:22])=[CH:10][CH:11]=2)[C:6]1=[O:23]
Reactant: O=c1c2cc(F)ccc2cc(-c2ccc(O)cc2)n1Cc1ccc(F)cc1F
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c2cc(F)ccc2cc(-c2ccc(Oc3ccccc3)cc2)n1Cc1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 45 %

Procedure:
To a solution of 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-hydroxyphenyl)-2H-isoquinolin-1-one (54 mg, 0.14 mmol), a compound of formula (Id), in CH2Cl2 (8 mL) was added phenylboronic acid (35 mg, 0.28 mmol), copper (II) acetate (51 mg, 0.28 mmol), and powdered activated 4 Å molecular sieves (500 mg). The mixture was stirred for 10 minutes then treated with triethylamine (99 μL, 0.71 mmol). The resulting suspension was stirred for 72 hours at ambient temperature. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography on silica gel eluting with 25% EtOAc/hexanes to afford 2-(2,4-difluorobenzyl)-7-fluoro-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one, a compound of formula (Id), (29 mg, 45% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 8.11 (1H, dd, J=9.4, 2.8 Hz), 7.52 (1H, dd, J=8.6, 5.1 Hz), 7.45-7.36 (3H, m), 7.19-7.14 (1H, m), 7.14-7.09 (2H, m), 7.08-7.03 (2H, m), 7.02-6.93 (3H, m), 6.78-6.72 (1H, m), 6.70-6.64 (1H, m), 6.47 (1H, s), 5.24 (2H, s) ppm.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][N:12]([CH3:29])[C:13]1[CH:28]=[CH:27][C:16]([CH2:17][O:18][C:19]2[CH:20]=[C:21]([C:25]#[CH:26])[CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1.CON(C)[C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>O1CCCC1>[C:34]1([C:33](=[O:40])[C:26]#[C:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH2:17][C:16]3[CH:27]=[CH:28][C:13]([N:12]([CH3:11])[CH3:29])=[CH:14][CH:15]=3)[CH:20]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CON(C)C(=O)c1ccccc1
Reactant: C#Cc1cccc(OCc2ccc(N(C)C)cc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CN(C)c1ccc(COc2cccc(C#CC(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Place lithium hexamethyldisilazane (2 mL of a 1M solution in tetrahydrofuran, 2 mmol) and tetrahydrofuran (8 mL) under an argon atmosphere and cool to 0° C. Add a solution of 3-(4-(dimethylamino)benzyloxy)phenylacetylene (0.51 g, 2 mmol) in tetrahydrofuran and stir the solution for 45 minutes at 0° C. Add N-methoxy-N-methylbenzamide (0.4 g, 2.4 mmol), remove the cooling bath and stir at room temperature for 1 hour. Partition the mixture between ethyl ether and water, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo to yield an oil. Filter through silica gel and elute with 10% ethyl acetate/hexane to yield a crude solid. Purify by silica gel chromatography to give the title compound.
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][C@H:3]([C:7]([NH:9][C@H:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH3:11])=[O:8])[NH:2]2.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:2]2[C@@H:3]([C:7]([NH:9][C@H:10]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:20][CH:21]=3)[CH3:11])=[O:8])[CH2:4][CH:5]3[CH:1]2[CH2:6]3)=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC3CC3N2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compounds (D150) (72 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((1S)-1-((3R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)ethyl)benzoate (D107) (48 mg) and 4-(trifluoromethyl)-benzylbromide (0.031 ml) (Na2CO3: 3 eq; Reaction time: 18 hrs; 68° C.)
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1[CH2:11]Br.[NH3:14]>CO>[Br:10][C:7]1[CH:6]=[C:5]2[C:4](=[CH:9][CH:8]=1)[C:3](=[O:2])[NH:14][CH2:11]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: N
Solvent: CO
Product: O=C1NCc2cc(Br)ccc21
Temperature: 40 °C
Yield: 89 %

Procedure:
4-Bromo-2-bromomethylbenzoic acid methyl ester (0.70 g, 2.3 mmol) and sat. NH3 in MeOH (3 mL) were placed in a sealed tube. The mixture was heated at 40° C. overnight. After cooling to rt, the solids were collected to afford 5-bromoisoindolin-1-one (0.43 g, 89%). 1H NMR (DMSO-d6, 400 MHz) δ 8.62 (br s, 1H), 7.81 (s, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 4.35 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:22])[CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.CCO.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15](=[O:22])[CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[O:7])=[CH:23][CH:24]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
A 3-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a dropping funnel, and a nitrogen inlet/outlet adapter was charged with ethyl 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoate (128.0 g, 370.2 mmol), EtOH (1.29 L), and KOH (27.7 g, 1444.2 mmol). The resulting mixture was stirred at 20° C. for 24 h. Additional KOH (1.12 g, 0.04 eq.) was added and the reaction was stirred for an additional 6 h. The resulting yellowish thick slurry was dissolved in deionized water (1.2 L) and then poured into a 12-L 4-neck flask equipped with an overhead stirrer that contained ice-water (6 L) in an ice-water bath. The aqueous pH was adjusted to pH 2-3 using 2 N aqueous HCl solution with fast stirring at 8-10° C. for 20 min. The solid in the resulting milky slurry was collected by filtration, washed with deionized water (100 mL), dried under air-suction for 20 h and then in a vacuum oven at 60° C. under hi-vacuum (20 mmHg) for 72 h to yield 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoic acid as a yellowish solid, which was used in the next step without further purification. (ES, m/z) 318, 320 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]1[N:11]([CH2:23][CH2:24][OH:25])[CH:12]=[C:13]([C:15]2[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=2)[N:14]=1.[H-].[Na+]>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:13]2[N:14]=[C:10]3[N:11]([CH2:23][CH2:24][O:25][C:2]4[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=43)[CH:12]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)cn2CCO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A solution of 2-[2-(4-chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (7.52 g, 20.7 mmol) in DMF (100 mL) was cooled to 0° C. and treated with sodium hydride (804 mg, 20.1 mmol), the reaction mixture stirred at 0° C. for 10 min then allowed to warm to RT and stirred for 72 h. Further sodium hydride (150 mg) was added and stirring continued until no starting material remained before removal of solvent in vacuo. The residue was dissolved in ethyl acetate and the resultant solution washed three times with saturated brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated in pentane/diethyl ether (5:1) to give the title compound as a brown solid (5.38 g, 79%). LCMS RT=2.86, [M+H]+ =327. 1H NMR 400 MHz (CDCl3) δ: 9.35 (1H, s), 7.87 (1H, s), 7.63 (1H, s), 6.37 (1H, s), 6.03-6.02 (1H, m), 4.54-4.53 (2H, m), 4.53-4.33 (2H, m), 3.99 (3H, s), 1.57 (6H, d, J=6.63 Hz).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10]([OH:14])([CH3:13])([CH3:12])[CH3:11].[CH2:15]([O:22][CH2:23][O:24][CH2:25][CH2:26][C@H:27]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:28](O)=[O:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Cu]Cl.ClCCl>[CH2:15]([O:22][CH2:23][O:24][CH2:25][CH2:26][C@H:27]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C:28]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CCOCOCc1ccccc1)C(=O)O
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CCOCOCc1ccccc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.9 %

Procedure:
(Step 4) To N,N′-diisopropylcarbodiimide (0.643 mL, 4.13 mmol), tert-butanol (0.415 mL, 4.34 mmol) and copper(I) chloride (20 mg, 0.21 mmol) were added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, through Celite (registered trademark), and the solvent in the filtrate was evaporated under reduced pressure. To the obtained residue, dichloromethane (7.4 mL) and (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoic acid (183 mg, 0.516 mmol) obtained in Step 3 were added, and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through Celite (registered trademark), and the solvent of the filtrate was evaporated under reduced pressure. The resulting residue was purified by thin-layer chromatography (ethyl acetate/n-hexane=1/20), whereby tert-butyl (S)-4-(benzyloxymethoxy)-2-(tert-butyldimethylsiloxy)butanoate (40 mg, 19%) was obtained.
Reaction SMILES: N([O-])=O.[Na+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH3:18])([CH3:17])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:8][CH:7]=1.[N-:26]=[N+:27]=[N-].[Na+]>O.Cl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:16]([CH3:17])([CH3:18])[O:15][C:14](=[C:19]([C:22]#[N:23])[C:20]#[N:21])[C:13]=2[C:24]#[N:25])=[CH:10][CH:11]=1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1c1ccc(N=[N+]=[N-])cc1
Reaction time: 0.77 h

Procedure:
A solution of NaNO2 (0.69 g, 10.0 mmol) in 10 mL water was added dropwise to a solution of 2-[4-(4-aminophenyl)-3-cyano-5,5-dimethyl-5H-furan-2-ylidene] malononitrile (1.4 g, 5.0 mmol) in 30 mL 4M HCl at 0-5° C. After stirring the mixture at this temperature for 46 min, a solution of NaN3 (0.53 g, 8.0 mmol) in 10 mL water was added dropwise to the mixture at the same temperature. Stirring was continued for 1 h below 5° C. and then at room temperature overnight. The precipitate formed was filtered off, washed with water and air-dried. The yellow product was recrystallized from dichloromethane/1-propanol. Yield: 1.25 g (82%). Mp; 184° C. IR (neat) 3056, 2990, 2235, 2122, 2091, 1601, 1568 cm−1; 1H NMR (400 MHz, DMSO) δ 7.90 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 1.86 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 177.1, 176.6, 145.0, 130.61, 123.4, 120.30, 112.35, 111.4, 111.3, 101.60, 100.30, 55.20, 24.90; Anal, Calcd for C16H10N6O: C, 63.57; H, 3.33; N, 27.80. Found: C, 63.51H, 3.44; N, 27.20; UV-Vis (CH2Cl2): λmax=384 nm ε=2.9×104 L.mol−1cm−1.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:7]([C:9]2[N:10]=[CH:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:13]=2)[OH:8])=[CH:4][S:5][CH:6]=1>C(Cl)Cl.O=[Mn]=O>[CH3:1][C:2]1[C:3]([C:7]([C:9]2[N:10]=[CH:11][N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]=2)=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Cc1cscc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cscc1C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (4-methylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, B2, (6.5 g, 14.9 mmol) in 100 mL of CH2Cl2 was added MnO2 (13 g). The mixture was stirred at room temperature for 3 hr and then filtered through Dicalite and the solvent was evaporated in vacuo to give (4-methylthien-3-yl)-1-trityl-imidazol-4-yl-methanone, A3. 1H NMR (CDCl3) supported the assigned structure. ##STR41##
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(O)C.O>[CH2:13]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[C:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:1]2=[O:10])=[CH:22][CH:21]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCc2ccccc21
Reactant: CCCCCCOc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCOc1ccc(C=C2Cc3ccccc3C2=O)cc1
Reaction time: 0.33 h

Procedure:
1-Indanone (4.17 g, 0.032 mol) was dissolved in ethanol (20 ml), and was added to sodium hydroxide (0.44 g, 0.011 mol) dissolved in water (8 ml) and ethanol (3 ml) and was left to stir for 20 min. 4-(Hexyloxy)benzaldehyde (6.4 ml, 0.031 mol), dissolved in ethanol (35 ml), was added to the mixture and was stirred for 4 hours. The product was isolated by vacuum filtration and was washed with cold ethanol (2×20 ml) and was dried in a vacuum oven. Yield=8.47 g, 85%. 1H NMR and 13C NMR gave expected signals.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:18][CH2:17]3)[CH3:15])=[N:11][NH:10][C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.CI>CC#N>[CH:1]1([CH2:7][N:8]2[C:12]([CH2:13][CH:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[CH2:18][CH2:17]3)[CH3:15])=[N:11][N:10]([CH3:31])[C:9]2=[O:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: COc1ccccc1N1CCN(C(C)Cc2n[nH]c(=O)n2CC2CCCCC2)CC1
Solvent: CC#N
Solvent: CI
Product: COc1ccccc1N1CCN(C(C)Cc2nn(C)c(=O)n2CC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 48 %

Procedure:
To a slurry of 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-2,4-dihydro-3H-1,2,4-triazol-3-one D14 (50 mg, 0.121 mmol) and PS-BEMP (83 mg, 0.1820 mmol, 2.2 mmol/g) in MeCN (2 mL), MeI (11.5 μL, 0.182 mmol) was added and the mixture was shaken at room temperature for 64 h. The resin was filtered and the filtrate was evaporated under reduced pressure. The resulting yellow oil was purified by flash chromatography (Biotage Isolute SI, 1 g column, gradient DCM to 1% MeOH in DCM) and afforded 25 mg (48%) 4-(cyclohexylmethyl)-5-{2-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one E37 as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([NH2:15])[C:11]([NH2:14])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:18]([CH2:22][C:23](Cl)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(O)C>[NH2:15][C:10]1[CH:9]=[C:8]([O:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[NH:14][C:23](=[O:24])[CH2:22][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1N
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCO
Product: CC(C)(C)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1N
Temperature: 4.5 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(4-fluoro-benzyloxy)-benzene-1,2-diamine (0.23 g, 1 mmol) and N,N-diisopropylethyllamine (0.21 ml, 1.2 mmol) in 8 ml of anhydrous ethanol was added dropwise tert-butylacetylchloride (111 μl, 1 mmol) at 4-5° C. in an ice-water bath. The reaction mixture was stirred for 30 min at 4-5° C. and for 3 hours at room temperature. The solvent was removed in vacuo and the residue was chromatographied (hexane/ethyl acetate, 2:1) to give the desired product as a white solid. 1H-NMR (300 MHz, DMSO-d6): δ 8.94 (brs, 1H, exchangeable with D2O, NH), 7.44 (dd, J=5.7 and 8.7 Hz, 2H), 7.18 (t, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 1H), 6.34 (d, J=2.7 Hz, 1H), 6.18 (dd, J=8.7 and 2.7 Hz, 1H), 4.95 (s, 2H), 4.79 (brs, 2H, exchangeable with D2O, NH2), 2.13 (s, 2H), 1.00 (s, 9H). MS: 331 (M+1).
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]2[C:5]([CH2:6][CH2:7][C:8]3([C:16]42[N:20]=[C:19]([NH2:21])[C:18]([CH3:22])=[N:17]4)[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)[C:29]#[N:30]>>[NH2:21][C:19]1[C:18]([CH3:22])=[N:17][C:16]2([C:23]3[C:5](=[CH:4][CH:3]=[C:2]([C:32]4[CH:31]=[C:28]([CH:27]=[C:26]([Cl:25])[CH:33]=4)[C:29]#[N:30])[CH:24]=3)[CH2:6][CH2:7][C:8]32[CH2:13][CH2:12][CH:11]([O:14][CH3:15])[CH2:10][CH2:9]3)[N:20]=1
Reactant: CC1(C)OB(c2cc(Cl)cc(C#N)c2)OC1(C)C
Reactant: COC1CCC2(CCc3ccc(Br)cc3C23N=C(C)C(N)=N3)CC1
Product: COC1CCC2(CCc3ccc(-c4cc(Cl)cc(C#N)c4)cc3C23N=C(C)C(N)=N3)CC1

Procedure:
The title compound was prepared following the procedure described for Example 2, starting from 7′-bromo-4-methoxy-5″-methyl-3′,4′-dihydrodispiro[cyclohexane-1,2′-naphthalene-1′,2″-imidazol]-4″-amine (Example 5, 125 mg, 0.32 mmol) and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate 4, 93 mg, 0.35 mmol). The product was purified using preparative chromatography followed by concentration of the fractions, extraction of the remaining aqueous phase with DCM, washing the organic layer with water and concentration and drying in vacuo at 50° C. for 2 days to give:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Cl-].[O:10]=[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[CH2:13][NH+:12]1[CH3:20].C(=O)(O)[O-].[Na+]>O>[O:10]=[C:11]1[N:16]([CH3:17])[C:15](=[O:18])[N:14]([CH3:19])[CH:13]([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[OH:8])[N:12]1[CH3:20]
Reactant: Nc1cccc(O)c1
Reactant: CN1C[NH+](C)C(=O)N(C)C1=O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1C(=O)N(C)C(c2ccc(N)cc2O)N(C)C1=O

Procedure:
10.9 (0.1 mol) of m-aminophenol are added to a solution of 19.1 g (0.1 mol) of 2,4-dioxo-1,2,3,4-tetrahydro-1,3,5-trimethyl-s-triazinium chloride in 50 ml of water and the mixture is stirred for some minutes until a clear solution has been produced. 8 g of sodium bicarbonate are then added. 24 g (85) of the same compound as in Example 5 precipitate.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl:13][S:14](O)(=[O:16])=[O:15]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([S:14]([Cl:13])(=[O:16])=[O:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2ccccc21
Product: CC(=O)N1CCc2cc(S(=O)(=O)Cl)ccc21
Temperature: 60 °C

Procedure:
A 1.02 g portion of 1-acetylindoline was treated with 2 mL of chlorosulfonic acid at 0° C. The mixture was heated at 60° C. for 2 h, then treated with crushed ice, filtered and dried to give 1.3 g of the title compound which was used directly for subsequent reaction. TLC: Rf=0.18, 50% EtOAc/hexane. (1H)-NMR (CDCl3) consistent with structure.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2([F:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[S:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:14][C:8]1([C:7]2[C:2]([O:31][C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:16]4[S:15][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=5[N:17]=4)=[CH:30][CH:29]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: FC1(c2cccnc2Cl)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: FC1(c2cccnc2Oc2ccc(Nc3nc4ccccc4s3)cc2)CCOCC1
Temperature: 90 °C

Procedure:
To 2-chloro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyridine (0.11 g, 0.510 mmol) was added to 4-(benzo[d]thiazol-2-ylamino)phenol (0.124 g, 0.510 mmol) with cesium carbonate (0.332 g, 1.020 mmol) in DMSO (1 mL). The resulting mixture was heated to 90° C. overnight. Aqeuous work up and purification by prep-plate TLC (3% MeOH/DCM) produced desired product. MS (ESI, pos. ion) m/z: 422 (M+1). IC50 (uM) +++++.