Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:9]=1[OH:15].Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[O:29][CH3:30])[CH2:22][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=2)[C:9]=1[OH:15]
Reactant: COc1cc(COc2cccc(O)c2O)cc(OC)c1
Reactant: COc1ccc(CBr)cc1OC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(COc2cccc(OCc3ccc(OC)c(OC)c3)c2O)cc(OC)c1
Yield: 31.9 %

Procedure:
3-(3,5-Dimethoxybenzyloxy)-benzene-1,2-diol (0.28 g, 1.03 mmol), 4-bromomethyl-1,2-dimethoxy-benzene (0.24 g, 1.03 mmol), potassium carbonate (0.14 g, 1.03 mmol) and 18-crown-6-ether (0.03 g, 0.11 mmol) were stirred together at room temperature in acetone (30 cm3, 99%) under nitrogen for 21 hours. The solution was evaporated under reduced pressure, and the residue was taken up in dichloromethane (10 cm3) and water (10 cm3). The aqueous layer was extracted with dichloromethane (2×10 cm3), and the combined extracts were washed with water (2×40 cm3), dried (MgSO4), and evaporated under reduced pressure. The residue was taken up in diethyl ether (30 cm3) and washed with sodium hydroxide (2×15 cm3, 3% aqueous solution). The sodium hydroxide portion was saturated with solid carbon dioxide pellets and extracted with diethyl ether (3×30 cm3). The extracts were evaporated under reduced pressure to give a crude oil. The oil was chromatographed (SiO2, heptane:ethyl acetate, 1:1) to give the phenol, (0.14 g, 31%) as a clear oil.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:12]=1.C(O)(=O)C>COCCOC>[CH3:27][C:25]1[NH:24][N:23]=[C:22]([NH:21][C:13]2[N:12]=[C:11]([S:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:20]3[C:15]([CH:14]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:26]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccccc3)n2)n[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
NaH (155 mg) was added to a solution of benzenethiol (500 mg) in DME (2 ml) and the mixture was stirred for 1 hour at room temperature. (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg) was then added, and the resulting mixture was heated at 150° C. for 30 minutes under microwave irradiation. The reaction mixture was acidified to pH=7 with acetic acid and purified by preparative LC-MS to give 20 mg of (5-methyl-1H-pyrazol-3-yl)-(1-phenylsulfanyl-isoquinolin-3-yl)-amine as a yellow solid. LC-MS: m/e 333(MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15]C)=[N:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1)[CH3:2].[I-].[Na+].C(#N)C.Cl[Si](C)(C)C>O>[CH2:1]([C:3]1[C:4](=[O:15])[NH:5][C:6]([CH3:14])=[C:7]([N:9]2[CH:13]=[CH:12][CH:11]=[N:10]2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(-n2cccn2)c(C)nc1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCc1cc(-n2cccn2)c(C)[nH]c1=O
Temperature: 65 °C
Reaction time: 13 h
Yield: 81.6 %

Procedure:
To a mixture of 3-ethyl-2-methoxy-6-methyl-5-pyrazol-1-yl-pyridine (98 mg, 0.452 mmol) and sodium iodide (203 mg, 1.35 mmol) under a N2 atmosphere is added anhydrous acetonitrile (3 mL) followed by dropwise addition of chlorotrimethylsilane (170 μL, 1.35 mmol). The reaction mixture is stirred at 65° C. under nitrogen for 13 h. The reaction mixture is allowed to cool, diluted with water and the resulting mixture is extracted with 3 portions of dichloromethane. The combined extracts are dried over magnesium sulfate and evaporated to leave an orange residue. The crude product is triturated with ether/heptane to give 3-ethyl-6-methyl-5-pyrazol-1-yl-1H-pyridin-2-one as a light orange solid (75 mg, 82% yield). This material (30 mg) is dissolved in dichloromethane (2 mL) and treated with ethereal hydrochloric acid (2.0 M, 0.444 mL). The mixture is stirred for 1.5 h, evaporated and triturated with ether to give 3-ethyl-6-methyl-5-pyrazol-1-yl-1H-pyridin-2-one hydrochloride (29 mg) as a white powder. LC/MS: RT: 2.15 min, MS: m/e=204 (M+H); 1H NMR (CDCl3, δ ppm): 7.73 (1H, d), 7.55 (1H, d), 7.47 (1H, s), 6.47 (1H, t), 2.62 (2H, q), 2.33 (3H, s), 1.22 (3H, t).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([OH:17])[CH2:16][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].FC(F)(F)CO>[CH2:9]1[NH:8][CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([OH:17])[CH2:16][C@H:10]12
Reactant: [H][H]
Reactant: O[C@H]1C[C@@H]2CN(Cc3ccccc3)CCN2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: OCC(F)(F)F
Product: O[C@H]1C[C@@H]2CNCCN2C1

Procedure:
A mixture of (7S,8aR)-2-benzyloctahydropyrrolo[1,2-a]pyrazin-7-ol (Example 65D, 5 g, 21.52 mmol) and 2,2,2-trifluoroethanol (50 mL) was added to 20% palladium hydroxide on carbon, wet (0.500 g) in a pressure bottle. The mixture was stirred at 50° C. for 16 hours under 30 psi of hydrogen. The mixture was filtered through a nylon membrane to give a crude intermediate (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol. The title compound was prepared according to the procedure described in Example 61 substituting (7S,8aR)-octahydropyrrolo[1,2-a]pyrazin-7-ol for (7R,8aS)-octahydropyrrolo[1,2-a]pyrazin-7-ol. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43-1.63 (m, 2H), 2.10-2.27 (m, 3H), 2.50 (m, 1H), 2.80-3.00 (m, 2H), 3.20-3.50 (m, 2H), 4.22 (m, 1H), 4.42-4.60 (m, 1H), 4.80 (m, 1H), 7.70 (m, 3H), 7.82 (m, 1H); MS (ESI) m/z 315 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]([CH2:23]O)[N:22]=2)[CH2:14][C@@H:13]1[O:30][CH3:31])=[O:10].C1(P([N:46]=[N+:47]=[N-:48])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:46]([CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][C@@H:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[C@@H:13]([O:30][CH3:31])[CH2:14]2)[S:19][C:20]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N+:47]=[N-:48]
Reactant: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of ethyl 2-((3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-(hydroxymethyl)-1,3-thiazole-5-carboxylate (0.10 g, 0.2 mmol, Example 143) in anhydrous toluene was added diphenylphosphorylazide (0.053 mL, 0.24 mmol). The reaction was cooled to 0 deg and DBU was added slowly. After stirring at 0 deg for 30 min the reaction was warmed to room temperature and stirred overnight. The biphasic reaction mixture was washed with water (×3), 1NHCl (×1), brine (×1), dried with MgSO4 and concentrated (0.048 g). MS (ES) M+H: 516 for C19H23Cl2N7O4S.
Reaction SMILES: O.[OH-].[Na+:3].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O:18]CC)=[O:17])[CH:12]=2)[CH:7]=[CH:6][N:5]=1>CO>[Na+:3].[CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH:15]([CH2:21][CH2:22][CH3:23])[C:16]([O-:18])=[O:17])[CH:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CCCC(Oc1ccc2ccncc2c1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCC(Oc1ccc2ccncc2c1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 42 h

Procedure:
10 ml of water and 840 mg (21.0 mmol) of sodium hydroxide are added to a solution of 5.20 g (19.0 mmol) of ethyl 2-(isoquinolin-7-yloxy) -pentanoate in 50 ml of methanol, and the mixture is stirred at room temperature for 42 hours. The solvent is removed by distillation, giving 2-(isoquinolin-7-yloxy)pentanoic acid sodium salt as a colourless solid; ESI 246.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(F)cc1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(F)cc3)n2)c1

Procedure:
Intermediate 4 was coupled with 2-(4-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 458. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.1 (m, 3H) 7.7 (m, 1H) 7.5 (m, 2H) 7.2 (m, 2H) 6.9 (m, 2H) 4.5 (s, 2H) 3.8 (m, 2H) 3.7 (m, 1H) 3.4 (m, 2H) 2.9 (m, 7H) 1.9 (s, 2H).
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]([CH2:24][CH2:25][OH:26])[CH:12]=[C:13]([C:15]2[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=2)[N:14]=1.[H-].[Na+].O>CN(C=O)C>[CH:21]([N:16]1[C:15]([C:13]2[N:14]=[C:10]3[N:11]([CH2:24][CH2:25][O:26][C:2]4[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=43)[CH:12]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: COc1cc(Cl)c(-c2nc(-c3nc(C)nn3C(C)C)cn2CCO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cn1)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A solution of 2-[2-(4-chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (2.25 g, 5.97 mmol) in DMF (30 mL) was cooled to 0° C. and treated with sodium hydride (239 mg, 5.97 mmol), the reaction mixture stirred at 0° C. for 30 min then allowed to warm to RT and stirred for 2 h. The reaction mixture was re-cooled to 0° C. and treated with water (400 mL), the precipitated product filtered off and washed with water then dried in vacuo to give the title compound as a white solid (1.02 g, 50%). LCMS RT=2.68 min, [M+H]+=341. 1H NMR 400 MHz (DMSO-d) δ: 9.15 (1 H, s), 7.87 (1 H, s), 6.42 (1 H, s), 5.84 (1 H, m), 4.57-4.56 (4 H, m), 3.89 (3 H, s), 2.25 (3 H, s), 1.46 (6 H, d, J=6.60 Hz).
Reaction SMILES: [Na].Cl[C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[OH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>CO>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([O:12][C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:14][CH:15]=1)#[N:18]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: [Na]
Solvent: CO
Product: N#Cc1ccc(Oc2ncccc2C(=O)O)cc1
Reaction time: 6 h
Yield: 49.6 %

Procedure:
To a solution of 6.9 g of metallic sodium in 90 ml of methanol are added 24 g of 2-chloronicotinic acid and 18 g of 4-hydroxybenzonitrile. The methanol is distilled off under reduced pressure, 60 ml of nitrobenzene is added, and the mixture is allowed to stand at 180° C to 190° C for 6 hours. After cooling, an aqueous potassium carbonate solution is added to the reaction mixture, and the whole mixture is filtered off. The aqueous layer is separated, washed with ethyl acetate and made acid with hydrochloric acid. The crystalline precipitate is recrystallized from aqueous ethanol to give 18 g of 2-(4-cyanophenoxy)nicotinic acid melting at 198° C to 200° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](F)[CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.O.[CH:32]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:37][CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(F)c2)cc1
Reactant: NC1CCCC1
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2nc3c(Cl)cccn3c2-c2ccnc(NC3CCCC3)c2)cc1
Temperature: 150 °C
Yield: 76 %

Procedure:
8-Chloro-2-(4-fluorophenyl)-3-(2-fluoro-4-pyridinyl)imidazo[1,2-α]pyridine (0.10 g, 0.29 mmol) was dissolved in cyclopentylamine (5 mL). This solution was heated in a glass tube at 150° C. for 72 hours. Ethyl acetate and water were added to the reaction mixture and the phases were separated. The organic phase was washed with water, dried (magnesium sulfate), filtered and concentrated to a solid. This solid was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give 4-[8-chloro-2-(4-fluorophenyl)imidazo[1,2-α]pyridin-3-yl]-N-cyclopentyl-2-pyridinamine (90 mg, 76%) as a white foam. 1H NMR (CDCl3): δ 8.26 (d, 1H), 8.06 (d, 1H), 7.73 (q, 2H), 7.34 (d, 1H), 7.05 (t, 2H), 6.77 (t, 1H), 6.65 (dd, 1H), 6.4 (s, 1H), 4.85 (d, 1H), 3.92 (m, 1H), 2.0–1.4 (m, 8H); 19F NMR (CDCl3) δ −114.07; MS m/z 407 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:19]=[C:11]3[C:12]4[C:17]([CH2:18][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1.[O-][CH2:21][CH3:22].[Na+].C(I)C>C(O)C>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:19]=[C:11]3[C:12]4[C:17]([CH2:18][N:10]3[N:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: Oc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCI
Product: CCOc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
2-(3-Hydroxyphenyl)-5H-s-triazolo[5,1-a] isoindole (1.25 g, 0.05 mole) is added to 20 ml of ethanol containing one equivalent proportion of sodium ethoxide. To this mixture is added 0.49 ml (0.06 mole) of ethyl iodide in 5 ml of ethanol. After stirring for one hour at room temperature, a further amount of 0.49 ml of ethyl iodide is added. After refluxing for one hour the solvent is distilled off and the residue is washed with water and extracted with dichloromethane. Evaporation of the solvent and crystallization of the residue from ethanol gives 1 g (73%) of the title product, m.p. 166°-7° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To chloroacetyl chloride (3.0 mL, 37.7 mmol) in dry DCM (100 mL) was added 2-aminobenzyl alcohol (4.3 g, 34.9 mmol) followed by addition of diisopropylethylamine (13.0 mL, 78.6 mmol). The mixture was stirred at ambient temperature for 2 hrs. The mixture was quenched with saturated sodium bicarbonate. The organic layer was separated and washed with sat NaHCO3 (50 mL) and water (50 mL×2). The resulting solution was dried over MgSO4 and evaporated to afford 2-chloro-N-(2-hydroxymethyl-phenyl)acetamide as a brown oil in quantitative yield (7.0 g). MS: 182.0 (M−H2O)+; tR=1.46 min (method 1).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[PH:9](=[O:11])[O:10][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>C(#N)C>[C:16]([CH2:17][CH2:18][P:9]1(=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[O:10]1)#[N:19]
Reactant: C=CC#N
Reactant: O=[PH]1Oc2ccccc2-c2ccccc21
Solvent: CC#N
Product: N#CCCP1(=O)Oc2ccccc2-c2ccccc21
Reaction time: 1 h
Yield: 96.6 %

Procedure:
108 g (0.5 mol) of 6H-dibenz-[c,e][1,2]-oxaphosphorin-6-one are heated to 165° C. with stirring and under an inert-gas atmosphere, and 26.5 g (0.5 mol) of acrylonitrile are added dropwise over 4 hours. The mixture is stirred further at this temperature for 1 hour and then cooled, giving 134 g of a resinous composition. Digestion with a little acetonitrile produces 130 g of 6-(2-cyanoethyl)-(6H)-dibenz[c,e][1,2]-oxaphosphorin 6-oxide, which, after recrystallization from a little acetonitrile, has a melting point of 120-123° C. The yield is 97% of theory.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1>O>[C:1]([NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)(=[O:3])[CH3:2]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C

Procedure:
Acetic anhydride (7.lml) was added to a suspension of 4-amino-2,6-dichlorophenol (5.34 g) in-water (50 ml). The mixture was stirred at reflux for 2 hours. The reaction mixture was cooled to ambient temperature and the crude product was collected by filtration, washed with water and then washed with pentane to give 4-acetamido-2,6-dichlorophenol as a solid (5.6 g), m.p. 151°-152°; NMR ([CD3 ]2SO): 2.0(3H,s), 7.58(2H,s) and 9.92(2H,br s); m/z 220 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=O)[CH:7]=[CH:6]2.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[Na]>O1CCCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[CH:7]=[CH:6]2
Reactant: C1CCNC1
Reactant: COc1ccc2cc(C=O)ccc2c1
Agent: [Na]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2cc(CN3CCCC3)ccc2c1
Temperature: 0 °C
Reaction time: 7 h
Yield: 100.1 %

Procedure:
To a solution of 6-methoxy-2-naphthaldehyde (3.00 g, 16.1 mmol) and pyrrolidine (2.69 ml, 32.2 mmol) in tetrahydrofuran (32 ml) and acetic acid (16 ml) was added sodium triacetoxyhydroborate. (6.83 g, 32.2 mmol) at 0° C., and the mixture was stirred at room temperature for 7 hours. The solvent was distilled off under reduced pressure, 1N hydrochloric acid was added to the resulting oil, and the mixture was washed with diethyl ether. An 8N aqueous sodium hydroxide solution was added to the aqueous layer, followed by extraction with ethyl acetate. The extract was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain the titled compound (3.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32](Cl)=[O:33]>C1COCC1>[CH3:28][O:29][C:30]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:31]=1[C:32](=[O:33])[CH:13]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([F:11])([F:10])[F:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Reactant: COC(=O)Cc1ccc(C(F)(F)F)c(OC)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(C(=O)c1cc(OC)ccc1OC)c1ccc(C(F)(F)F)c(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of methyl 2-(3-methoxy-4-(trifluoromethyl)phenyl)acetate (18.6 g, 75 mmol) in anhydrous THF (250 mL) at −78° C., LiHMDS (1.0 M in THF, 79 mL, 79 mmol) was added dropwise under N2. The resulting mixture was stirred at −78° C. for 30 minutes, and a solution of 2,5-dimethoxybenzoyl chloride (15.9 g, 78 mmol; intermediate in Intermediate 1) in anhydrous THF (50 mL) was added dropwise. The reaction mixture was stirred for another 1 h at −78° C., quenched with saturated aqueous NH4Cl (100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (30.1 g). 1H NMR (DMSO-d6): δ 7.50 (d, 1H), 7.34 (d, 1H), 7.09-7.07 (m, 1H), 6.94-6.87 (m, 3H), 5.71 (s, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 3.77 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)C1C=CC=CC=1.CO.[H][H]>[Pd].CCOC(C)=O>[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:12]2[C:11]([NH2:10])=[CH:16][CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:13]=2)=[O:35])=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2N)cc1

Procedure:
A solution of benzyl(2-{[4-(acetylamino)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate from the previous step (30 mg theoretical, 0.0626 mmol) and MeOH (100 uL) were treated with 10% palladium on carbon (cat) and the reaction was fitted with a hydrogen balloon. After one hour the reaction was diluted with EtOAc, filtered through celite and concentrated to a residue purified via reversed phase HPLC (30-70% MeCN in water with 0.05% TFA) to afford fractions concentrated via sublimation to afford the title compound as a light yellow solid and a TFA salt. 1H NMR (MeOH-d4, 600 MHz) δ 8.04 (d, J=8.8 Hz, 2H), 7.87 (d, J=7.3 Hz, 2H), 7.76 (t, 8.2 Hz, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (t, J=7.6 Hz, 2H), 7.45 (d, J=7.3 Hz, 1H), 2.18 (s, 3H); MS cal'd (M+H)+, exp 347 (M+H)+. The in vitro HDAC1 IC50 of this compound is 86 nM. The IC50 of this compound in HCT-116 cells is 2050 nM.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:9]([NH2:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13]
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(O)c1N
Yield: 131.8 %

Procedure:
2,3-dinitrophenol (80%) 25 g (0.11 mol) was dissolved in 700 ml ethanol and 0.5 g Pd/C was added. The mixture was hydrogenated at room temperature until the uptake of hydrogen ceased (4 h). The solution was filtered (celite) in N2 -atmosphere and evaporated to dryness in vacuo to give the title compound as an unstable oil (18 g), which was used immediately for the next step.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH:14]([C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=1>ClCCl>[CH3:8][S:9]([O:13][CH:14]([C:42]1[CH:43]=[CH:44][C:45]([C:46]#[N:47])=[CH:48][CH:49]=1)[CH2:15][O:16][CH2:17][C:18]1[N:19]=[CH:20][N:21]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4 mmol of triethylamine and 2.00 mmol of methanesulphonyl chloride are added to a solution of 1.00 mmol of 4-[1-hydroxy-2-(1-trityl-1H-imidazol-4-ylmethoxy)ethyl]benzonitrile in 10 ml of dichloromethane at 0° C. The reaction mixture is stirred at 0° C. for 1 hour, diluted with dichloro-methane, washed with 1N HCl, dried with sodium sulphate and evaporated. The crude title compound is used without further purification in the next stage. Rf=0.43 (dichloromethane-methanol 95:5); Rt=4.46 (gradient I).