Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:17])[O:12]2)=[CH:7][C:6]=1[CH:18]=[CH:19][O:20]C(=O)C)(=O)C.P(=O)(O)(O)O>>[CH3:16][O:15][C:14]1[C:13]2[O:12][C:11](=[O:17])[CH:10]=[CH:9][C:8]=2[CH:7]=[C:6]2[CH:18]=[CH:19][O:20][C:5]=12
Reactant: COc1c(OC(C)=O)c(C=COC(C)=O)cc2ccc(=O)oc12
Agent: O=P(O)(O)O
Product: COc1c2occc2cc2ccc(=O)oc12

Procedure:
A solution of 40 mg. (0.13 mmole) of 7-acetoxy-6-[2-acetoxyvinyl]-8-methoxycoumarin in 5 ml. of 85% phosphoric acid was heated at 90° for 30 minutes. The solution was cooled and partitioned between water/methylene chloride. The aqueous phase was further extracted with methylene chloride. The organic phases were combined, dried over sodium sulfate, and evaporated to afford pure 9-methoxy-7H-furo[3,2-g][1]benzopyran-7-one, mp 145°-146°, as a crystalline white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][C:11]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])=[C:10]([CH3:22])[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:25][CH3:26])[C:13]2[C:8](=[CH:9][C:10]([CH3:22])=[C:11]([C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCCC(=O)c1cc2c(=O)cc(C(=O)OCC)[nH]c2cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(=O)c1cc2c(OCC)cc(C(=O)OCC)nc2cc1C
Reaction time: 8 h

Procedure:
16.3 g of 6-Butyryl-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid ethyl ester are dissolved in 330 ml of dimethylformamide, and 2.6 g of a 50% strength sodium hydride dispersion in mineral oil are added. Stirring is carried out overnight at room temperature and then 8.7 ml of ethyl iodide are added dropwise, and the mixture is stirred for 2 hours at room temperature, concentrated under reduced pressure at 60°, poured onto ice, acidified and filtered with suction. 4-Ethoxy-6-butyryl-7-methylquinoline-2-carboxylic acid ethyl ester having a melting point of 123°-124° is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:36])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(C(=O)N3CCOCC3)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 60 °C

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 100 mg, 0.25 mmol) in dry DMF (5 mL), sodium hydride (12 mg, 0.27 mmol) was added at 0° C. under nitrogen atmosphere. After 15 minutes morpholine-4-carbonyl chloride (56.1 mg, 0.37 mmol) was added, and the reaction mixture was heated at 60° C. for 48 hours. The reaction mixture was concentrated in vacuum. The crude product was purified by column chromatography (silica gel, 3% acetone in chloroform) to obtain the title compound. Yield: 15 mg (11.73%); 1H NMR (CDCl3, 300 MHz): δ 9.09 (s, 1H), 7.973-8.004 (d, 1H, J=9.3 Hz), 7.772-7.8 (d, 2H, J=8.4 Hz), 7.621-7.658 (dd, 1H, J=9 Hz, 2.1 Hz), 7.517-7.545 (d, 2H, J=8.4 Hz,), 7.057-7.064 (d, 1H, J=2.1 Hz), 3.67 (t, 4H,), 3.26 (t, 4H), 1.84 (s, 6H); MS: m/z 520 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.CN(C=O)C.[Br:16][CH2:17][C:18](Br)=[O:19]>O1CCOCC1>[Br:16][CH2:17][C:18]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:19]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
A solution of 4-aminobenzoic acid (5.0 g, 36 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (7.27 g, 3.16 mL, 36 mmol) was then added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 7.46 g (81%) of the title compound as a white solid, mp 241°-243° C.: 1H NMR (DMSO-d6) δ12.79 (bs, 1H), 10.68 (s, 1H), 7.91 (d, J=9.2, 2H), 7.69 (d, J=9.2, 2H), 4.06 (s, 2H); 13C NMR (DMSO-d6) δ166.79, 165.28, 142.56, 130.47, 125.70, 118.53, 30.29; MS (EI, m/z) 259 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31]C1C=CC=CC=1CCl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Reactant: ClCc1ccccc1Cl
Product: OC(Cc1ccccc1Cl)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-Benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using 2-chlorobenzyl chloride (available from Aldrich Chemical Company) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=408 and 410.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[H-].[Na+].C(O)(=O)C.C([O:19][C:20]1[C:21]([CH2:30]O)=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1)(=O)C>CN(C)C=O>[OH:19][C:20]1[C:21]([CH2:30][S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])=[CH:22][C:23]2[O:28][CH2:27][CH2:26][CH2:25][C:24]=2[CH:29]=1
Reactant: OCc1ccccc1S
Reactant: CC(=O)Oc1cc2c(cc1CO)OCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: OCc1ccccc1SCc1cc2c(cc1O)CCCO2
Reaction time: 0.5 h

Procedure:
To a solution of o-mercaptobenzylalcohol (289 mg, 2.06 mmol) in dry dimethylformamide (3 mL) was added sodium hydride (60% dispersion in mineral oil, 83 mg, 2.07 mmol) portionwise and the mixture allowed to stir for 30 minutes. To the resulting solution was added dropwise a solution of 6-acetoxy-7-hydroxymethyl-3,4-dihydrobenzopyran acetate (543 mg, 2.06 mmol) in dry dimethylformamide and the mixture allowed to stir at room temperature under nitrogen for three hours, heated to 50° for 30 minutes, then allowed to cool and stir overnight. The reaction was quenched with 2.5N sodium hydroxide (2 mL) and after stirring for 30 minutes, the mixture was poured into water (75 mL). The aqueous mixture was neutralized with 2N hydrochloric acid (2.5 mL), extracted with ether (2×100 mL) and the ether extract washed with brine (3×100 mL), dried (Na2SO4) and concentrated. The crude product was purified by preparative HPLC (2:1 hexane/ethyl acetate as eluant) to afford 6-hydroxy-7-(2-hydroxymethylphenyl)thiomethyl-3,4-dihydrobenzopyran as a pale off-white solid, m.p. 140°-141° C.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1.[CH2:17](I)[CH2:18][CH3:19]>CS(C)=O>[CH2:17]([N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1)[C:11](=[O:16])[CH:12]=[C:13]([CH3:14])[CH3:15])[CH2:18][CH3:19]
Reactant: CC(C)=CC(=O)Nc1cccc(Br)c1
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCN(C(=O)C=C(C)C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
44.3 g of powdered potassium hydroxide were suspended in 200 ml of dimethyl sulphoxide and a solution of 50 g of N-(3-bromophenyl)-3,3-dimethyl-acrylamide in 300 ml of DMSO was added dropwise thereto. The mixture was stirred at room temperature for 1 hour and subsequently a solution of 50.3 g of propyl iodide in 200 ml of DMSO was added dropwise thereto. After 2 hours the reaction mixture was poured on to ice-water, extracted three times with ethyl acetate, the organic phase was washed several times with water, dried and evaporated. After filtration of the crude product over a silica gel column (eluent hexane/ethyl acetate 9:1), 58 g of N-propyl-N-(3-bromophenyl)-3,3-dimethyl-acrylamide were obtained as a yellow oil. This product was dissolved in 1.5 l of petroleum ether (high boiling). 52.3 g of aluminium chloride were added portionwise thereto while stirring and the mixture was subsequently heated at reflux for 2.5 hours. After cooling to 0°-5° C. 500 ml of ice-cold 1N hydrochloric acid were added dropwise thereto, the mixture was diluted with water and extracted several times with ether. The yellow oil obtained after drying and evaporation of the solvent was a 6:4 mixture of 5-bromo-3,4-dihydro-4,4-dimethyl-1-propyl-2(1H)-quinolinone. It was filtered over a silica gel column (eluent hexane/5% ethyl acetate) and taken up in a small amount of hexane. After seeding with the 7-bromo compound above, 12.2 g of pure 7-bromo-3,4-dihydro-4,4-dimethyl-1-propyl-2(1H)-quinolinone crystallized in the cold in colourless crystals, m.p. 50°-51° C.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([NH:16][C@@:17]1([C:27]([OH:29])=[O:28])[CH2:22][C:21](=[O:23])[C@@H:20]2[C@H:18]1[C@H:19]2[C:24]([OH:26])=[O:25])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[C:9]([O:13][C:14]([NH:16][C@@:17]1([C:27]([O:29][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])[CH2:22][C:21](=[O:23])[C@@H:20]2[C@H:18]1[C@H:19]2[C:24]([O:26][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:25])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)O)CC(=O)[C@H]2[C@H](C(=O)O)[C@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OCc2ccccc2)CC(=O)[C@H]2[C@H](C(=O)OCc3ccccc3)[C@H]21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Add benzyl bromide (8.69 mL, 72.9 mmol) dropwise to a stirred suspension of (1S,2S,5R,6R)-2-(tert-butoxycarbonylamino)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (7.27 g, 24.3 mmol) and cesium carbonate (15.83 g, 48.6 mmol) in dry N,N-dimethylformamide (60 mL). Stir the resulting mixture at room temperature overnight under nitrogen. Quench with water and dilute with ethyl acetate. Extract the aqueous phase with ethyl acetate (3 times) and wash the organic layers with brine and water. Dry over sodium sulfate, filter and concentrate to give the crude material as a pale brown oil. Purify by flash chromatography eluting with ethyl acetate:hexane (20:80 to 30:70) to give the title compound as gummy yellow foam (9.15 g, 78.5%). MS (m/z): 502 (M+23).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.[Mg].II.[C:16]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:3][CH:4]=1
Reactant: O=C1CCCC1
Reactant: Brc1ccc(C2OCCO2)cc1
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2ccc(C3OCCO3)cc2)CCCC1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-bromophenyl)-[1,3]dioxolane (1.15 g, 5.00 mmol) in THF (5.0 ml) is added dropwise at 55° C. to magnesium turnings (146 mg, 6.0 mmol) and a crystal of iodine in THF (5 ml). The mixture is stirred for 1 h at 55° C. Then a solution of cyclopentanone (465 μl, 5.25 mmol) in THF (5 ml) is added dropwise and the mixture is stirred for another hour at 55° C. The reaction mixture is diluted with THF, acidified with 1 N HCl (4 ml) and washed three times with brine. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 1-(4-[1,3]dioxolan-2-yl-phenyl)-cyclopentanol as yellow oil; HPLC/MS 1.71 min (A), [M+H] 235.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[CH3:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][NH2:23])=[N:18][CH:17]=[CH:16][N:15]=1>C(O)(C)C>[CH3:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][NH:23][CH2:7][CH:6]([OH:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[CH3:1])=[N:18][CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccccc1OCC1CO1
Reactant: Cc1nccnc1OCCN
Solvent: CC(C)O
Product: Cc1ccccc1OCC(O)CNCCOc1nccnc1C
Reaction time: 24 h

Procedure:
A solution of 4.92 g of 1-(o-methyl-phenoxy)-2,3-epoxypropane and 4.59 g of 2-methyl-3-(2-amino-ethoxy)pyrazine in 150 ml of isopropanol is stirred for 24 hours at about 20° C. and thereafter a further 1.47 g of 1-(o-methyl-phenoxy)-2,3-epoxy-propane are added. After standing for a further 24 hours at about 20° C., the reaction mixture is evaporated under a waterpump vacuum, the residue is dissolved in ether, the ether solution is extracted by shaking with 2 N hydrochloric acid and the combined hydrochloric acid extracts are rendered alkaline with sodium hydroxide solution and extracted by shaking with ether. The combined ether extracts are washed with water, dried over sodium sulphate and evaporated under a waterpump vacuum. The residue crystallises from methylene chloride/petroleum ether, giving 1-[2-(2-methyl-3-pyrazinyloxy)-ethyl-amino]-3-(2-methyl-phenoxy)-2-propanol; melting point 82°-84° C. The acid fumarate prepared with the calculated amount of fumaric acid crystallises from isopropanol, melting point 140°-141° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:12]([N+:20]([O-])=O)[CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[OH-].[Na+]>C(OCC)(=O)C>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[C:12]([NH2:20])[CH:11]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(S(C)(=O)=O)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(S(C)(=O)=O)c(N)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
Tin(II) chloride dihydrate (2.73 g, 12.1 mmol) was added to a solution of the above sulfone (777 mg, 3.02 mmol) in ethyl acetate (15 mL). The mixture was heated to reflux for 0.5 h then cooled to room temperature and poured onto aqueous 2.0 M NaOH. The aqueous phase was extracted with diethyl ether and the combined organic layers were washed with saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated in vacuo to provide pure 5-tert-butyl-2-methanesulfonyl-phenylamine (618 mg, 90%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:5]([CH2:6]N(C)C)=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17].[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[OH:1][C:2]1[C:11]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:10][C:5]([CH2:6][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCOP(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOP(=O)(Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)OCC
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
A thermostatically controllable reactor is charged with 553.8 g (2.1 mol) of (4-hydroxy-3,5-di-tert-butylbenzyl)dimethylamine und 450 g of petroleum ether 100/140. With stirring and blanketing with inert gas, the reaction mixture is heated to 60° C. and 366.4 g (2.2 mol) of triethyl phosphite are run into the clear solution. With cooling, 225.1 g (2.2 mol) of acetic anhydride are then added dropwise over 2 hours at 60° C., and stirring is continued for 1 hour at 60° C. The solvent is removed by distillation until the temperature is 115° C. The residual reaction solution is washed with 4×250 ml of water at 75° C. and dried by azeotropic distillation. Upon cooling to room temperature, the product crystallises and is filtered with suction, washed with petroleum ether 100/140 and dried, giving 693.2 g (92.6% of theory) of colourless diethyl 4-hydroxy-3,5-di-tert-butylbenzylphosphonate of m.p. 119°-121° C.
Reaction SMILES: [I-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][NH2:7].[O:8]([CH2:16][CH2:17]Br)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>C(O)C>[O:8]([CH2:16][CH2:17][NH:7][CH2:6][CH2:5][O:4][CH3:3])[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: COCCN
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: COCCNCCO[Si](C)(C)C(C)(C)C
Yield: 55 %

Procedure:
Sodium iodide (14.48 g) is added to a solution of 2-methoxyethylamine (14 ml) and 2-(t-butyldimethylsiloxy)ethyl bromide (7.00 g) in ethanol (65 ml), and the mixture is refluxed overnight with stirring. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the whole is extracted with chloroform. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 4.13 g (55%) of the titled compound (Reference compound No. 14-1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.[CH3:27][O:28][CH2:29][CH2:30][NH2:31]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:6]([NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:8]
Reactant: COCCN
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COCCNC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.3 %

Procedure:
To a solution of 3-methoxy-5-nitrobenzoic acid (1 g; 5.1 mmol; 1 eq) DCM (40 mL) is added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (972 mg; 5.1 mmol; 1 eq). After 5 min, 2-methoxyethylamine (381 mg; 5.1 mmol; 1 eq) is added and the reaction mixture is stirred at room temperature for 2 h. The reaction mixture is then quenched with water and the expected product extracted with EtOAc. The organic phase is washed with an aqueous solution of Na2CO3 then dried over MgSO4. The solvent is evaporated to dryness to afford (1.3 g (100%) of the title compound as an orange oil. HPLC (max plot) 73.0%; Rt 2.98 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[C:13](O)([C:15]([F:18])([F:17])[F:16])=O>>[Br:1][C:2]1[C:3]2[N:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Product: O=[N+]([O-])c1cc(Br)c2nc(C(F)(F)F)[nH]c2c1
Temperature: 85 °C
Yield: 53.1 %

Procedure:
In a 250 mL round-bottom flask a mixture of 3-bromo-5-nitrobenzene-1,2-diamine (10 g, 43.1 mmol) and TFA (23.24 mL, 302 mmol) was heated to 85° C. for 17 hours. The mixture was allowed to cool to RT, and then was concentrated in vacuo to remove the excess TFA. The residue was partitioned between water (100 mL) and ether (100 mL; not soluble in dichloromethane). The phases were separated, and the organic layer was dried over Na2SO4, then filtered and concentrated in vacuo to provide 4-bromo-6-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole (7.1 g, 22.90 mmol, 53.1% yield) as a brown solid. LCMS and NMR are consistent with structure (NMR contains a trace of ether). MS (ES+) m/e: 308.9, 310.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 15.09 (br. s., 1H) 8.49-8.66 (m, 1H) 8.36-8.48 (m, 1H)
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[CH:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:26].C([Li])CCC.CN(C)[CH:34]=[O:35].[Cl-].[NH4+]>C1COCC1>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[N:12]1[C:8]([CH2:7][O:6][C:5]2[CH:24]=[CH:25][C:2]([CH:34]=[O:35])=[C:3]([CH3:26])[CH:4]=2)=[C:9]([CH:21]([CH3:23])[CH3:22])[CH:10]=[N:11]1
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1C=O
Reaction time: 0.5 h
Yield: 14 %

Procedure:
To a −78° C. solution of 5-(4-Bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (906 mg, 2.0 mmol) in anhydrous THF is added 1.6 M n-butyllithium (1.35 mL). After 30 minutes, N,N-dimethylformamide is added (0.5 mL, 6.4 mmol). After 30 minutes, saturated aqueous ammonium chloride is added. The mixture is extracted with ethyl acetate (2×). The combined ethyl acetate layers are dried (MgSO4) and concentrated under reduced pressure. The crude residue is purified via flash chromatography (ethyl acetate/heptane gradient) to afford the title compound (110 mg, 14%). LC-ES/MS m/e 403.0 (M+1).
Reaction SMILES: [CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[CH:7][N:6]=2)[CH2:4][CH2:3][CH2:2]1.[I:15]N1C(=O)CCC1=O>CN(C)C=O>[CH:1]1([C:5]2[N:13]3[C:8]([C:9](=[O:14])[NH:10][CH:11]=[N:12]3)=[C:7]([I:15])[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: O=c1[nH]cnn2c(C3CCC3)ncc12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: O=c1[nH]cnn2c(C3CCC3)nc(I)c12
Temperature: 55 °C

Procedure:
A solution of 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (789 mg, 4.15 mmol) and N-iodosuccinimide (NIS, 933 mg, 4.15 mmol) in anhydrous DMF (40 mL) was stirred overnight at rt. An additional 4 eq. of NIS was added and reaction was heated to 55° C. for 6 h. The reaction mixture was concentrated in vacuo and partitioned between DCM and H2O and separated. The aqueous layer was washed with DCM (3×) and the combined organic fractions were washed with 1M sodium thiosulfate (Na2S2O3) (1×), brine (1×), dried over sodium sulfate (Na2SO4), filtered, and concentrated in vacuo. The solid was triturated with 20% EtOAc in DCM and filtered through a fritted Buchner funnel resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.84-1.96 (m, 1H), 1.98-2.13 (m, 1H), 2.25-2.43 (m, 4H), 3.84-3.96 (m, 1H), 7.87 (s, 1H); MS (ES+): m/z 317.02 (100) [MH+], HPLC: tR=2.62 min (MicromassZQ, polar—5 min).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[NH2:16]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:16][C:15]1[CH:17]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:19]=[C:13]([O:12][CH3:11])[CH:14]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: COc1cc(N)cc(C(F)(F)F)c1
Product: COc1cc(Nc2nc3ccccc3[nH]2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3-methoxy-5-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 212-213° C.). MS(ES+) m/z 308 ([M+1]+, 100).