Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[CH:6]3[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:7](=[O:17])[C:6]3([CH3:24])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1CC(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CC12COCCN1c1nc(Cl)ncc1N(CC(F)(F)F)C2=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.8 %

Procedure:
To a mixture of 2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (768 mg, 2.38 mmol) and iodomethane (0.595 ml, 9.52 mmol) in DMSO (15 ml) at 0° C. was added sodium 2-methylpropan-2-olate (343 mg, 3.57 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude oil. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 11:9) to afford 2-chloro-6a-methyl-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (191 mg, 0.566 mmol, 24% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 3H) 3.17-3.28 (m, 1H) 3.55 (td, J=12.13, 3.03 Hz, 1H) 3.68 (d, J=11.62 Hz, 1H) 3.89-4.07 (m, 3H) 4.75-5.04 (m, 2H) 8.31 (s, 1H). MS [M+H] found 337.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O[C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC)[CH2:16][CH3:17])C>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]([CH3:17])[C:4]2=[O:6]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CCOC(CC)(OCC)c1ccccc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1c(-c2ccccc2)[nH]c2ccc(Cl)cc2c1=O
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a mixture of 2-amino-5-chloro-benzoic acid (0.82 g, 4.80 mmol) in Dowtherm A (20 mL), was added the compound of Step A (1.0 g, 4.80 mmol). The mixture was warmed to reflux for 15 hours, then cooled to room temperature. Upon cooling, a white precipitate formed which was collected by filtration. The solid was triturated with diisopropyl ether followed by methylene chloride to give the title compound (0.58 g, 45%), m.p. 296-302° C. Anal. calcd. for C16H12CINO: C, 71.25; H, 4.48; N, 5.19. Found: C, 70.92; H, 4.44; N, 5.04.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)(=[O:3])N.[ClH:21].[OH2:22]>>[ClH:21].[ClH:21].[N:8]1([CH2:7][CH2:6][O:5][CH2:4][C:1]([OH:3])=[O:22])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCN(CCOCC(N)=O)CC1
Agent: Cl
Product: O=C(O)COCCN1CCNCC1
Temperature: 60 °C
Yield: 88 %

Procedure:
1 g (0.00348 mol) of tert-butyl 4-(2-carbamoylmethoxyethyl)piperazine-1-carboxylate prepared in Example I.4.3. and 2 ml of water are placed in a 10 ml conical flask. 2 ml of 37% hydrochloric acid solution are added and the mixture is heated on an oil bath at 60° C. for 1 hour. The water is eliminated on a rotary evaporator under reduced pressure. The residue is taken up in toluene. After evaporation, 1.1 g of a pale yellow solid are obtained. This finely ground solid is placed in a Buchi sublimator. The apparatus is placed under vacuum (0.3 mmHg) and heated at 150° C. for 8 hours. 800 mg (88%) of 2-(1-piperazinyl)ethoxyacetic acid dihydrochloride are obtained in the form of white crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:21]2[NH:22][C:23](=[O:30])[C:24]([CH:27]([CH3:29])[CH3:28])([CH3:26])[N:25]=2)=[C:7]([CH:20]=1)[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]C)=[O:17])=[O:9])[CH3:2].[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([C:21]2[NH:22][C:23](=[O:30])[C:24]([CH:27]([CH3:29])[CH3:28])([CH3:26])[N:25]=2)=[C:7]([CH:20]=1)[C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:9])[CH3:2]
Reactant: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)NCCCCCC(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)NCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of methyl 6-[5-ethyl-2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)nicotinamido]hexanoate (5.14 g, 12.35 mmol) in tetrahydrofuran is treated with 2N sodium hydroxide (15 mL). The resulting mixture is stirred at room temperature for 24 hours. After this period, the reaction mixture is concentrated in vacuo to obtain a residue. The residue is cooled with an ice bath and acidified with concentrated hydrochloric acid. The resulting precipitate is isolated by vacuum filtration and washed with water to give the title product as a white solid, mp 76°-81° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH3:11])[C:9]=1[Cl:10])=[O:4].[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([CH2:11][Br:12])[C:9]=1[Cl:10])=[O:4]
Reactant: COC(=O)c1scc(C)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: COC(=O)c1scc(CBr)c1Cl
Yield: 57.1 %

Procedure:
To 2-methoxycarbonyl-3-chloro4-methylthiophene (0.25 g, 1.3 mmol) in dry benzene (25 mL) were added N-bromosuccinimide (0.28 g, 1.6 mmol) and benzoyl peroxide (0.03 g, 0.13 mmol). The mixture was refluxed while irradiating with a 250 Watt lamp. After 2 hours the reaction was cooled and concentrated of all volatiles in vacuo. Purification by flash chromatography on silica gel afforded 0.20 g (58% yield) of 2-methoxycarbonyl-3-chloro-4-(bromomethyl)thiophene as a white solid; NMR (CDCl3) 7.6 (s, 1), 4.4 (s, 2), 3.9 (s, 3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[Br:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:16][CH2:17][CH2:18][CH2:19][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1CCCBr
Yield: 62.1 %

Procedure:
A suspension of ethyl 5-chloro-1H-indole-2-carboxylate (40 g, 0.18 mol), 1,3-dibromo-propane (181 g, 0.90 mol) and potassium carbonate (49.68 g, 0.36 mol) in 500 mL of acetone was heated under reflux for 16 hours. The mixture was concentrated in vacuo to remove the solvent and the residue was diluted with 1000 mL of water, then extracted with ethyl acetate (300 mL×2). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was purified by flash silica gel chromatography (EtOAc:PE=1:10) to afford 38.5 g of ethyl 1-(3-bromopropyl)-5-chloro-1H-indole-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]1([CH2:14][CH:15]([O:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH2:14][CH:15]([O:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)=[O:29])=[CH:31][CH:32]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc(OC(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: Nc1ccncc1
Product: O=C(Nc1ccncc1)c1ccc(OC(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
4-Aminopyridine 17-7 (0.471 g, 5 mmol) was acylated with 17-6 (1.75 g, 5 mmol) using the conditions of Example 13. The amide 17-8 was obtained as a solid foam.
Reaction SMILES: [CH2:1]=[C:2]([O:9][CH:10]1[CH:15]2[C:13]([N:16]3[CH:24]=[N:23][C:22]4[C:17]3=[N:18][C:19]([Cl:26])=[N:20][C:21]=4Cl)([CH2:14]2)[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:27]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28]1>CO>[CH2:1]=[C:2]([O:9][CH:10]1[CH:15]2[C:13]([N:16]3[CH:24]=[N:23][C:22]4[C:17]3=[N:18][C:19]([Cl:26])=[N:20][C:21]=4[NH:32][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)([CH2:14]2)[CH2:12][CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=C(OC1CCC2(n3cnc4c(Cl)nc(Cl)nc43)CC12)c1ccccc1
Reactant: NC1CCCC1
Solvent: CO
Product: C=C(OC1CCC2(n3cnc4c(NC5CCCC5)nc(Cl)nc43)CC12)c1ccccc1
Yield: 90 %

Procedure:
To a solution of 12 (42 mg, 0.105 mmol) in methanol (2 ml) was added cyclopentylamine at room temperature, and stirring was continued for 6 hr for complete reaction. Solvent was removed under vacuum, and the residue obtained was purified by flash column chromatography using 7/3 petroleum ether/ethylacetate as eluent to furnish 45 mg of the product 15 (90% yield) as a gum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].[CH2:15]([CH2:25]/[C:26](/[CH3:35])=[CH:27]/[CH2:28][CH2:29]/[C:30](/[CH3:34])=[CH:31]/[CH2:32]Br)/[CH:16]=[C:17](/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])\[CH3:18]>CN(C=O)C>[CH3:34]/[C:30](/[CH2:29][CH2:28]/[CH:27]=[C:26](\[CH3:35])/[CH2:25][CH2:15]/[CH:16]=[C:17](\[CH3:18])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[CH:31]\[CH2:32][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: O=c1ccc2cc(O)ccc2o1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/COc1ccc2oc(=O)ccc2c1
Temperature: 0 °C

Procedure:
An oven-dried 50 mL round bottom flask was prepared with a magnetic stirring bar, a rubber septum cover, and a nitrogen inlet. 6-hydroxycoumarin (1) (474 mg, 2.92 mmol) and 4 mL of anhydrous DMF were added to the round bottom flask. The solution was stirred and cooled to 0° C. in a salt-ice bath. Sodium hydride (117 mg of 60% mineral oil suspension, 2.93 mmol) was added and the solution was stirred at 0° C. for 30 minutes. The crude geranylgeranyl bromide (302.85 mg) from the previous step was dissolved in anhydrous DMF, cooled to 0° C. and added drop-wise to the flask through the rubber septum using a syringe. The reaction mixture was left stirring under nitrogen at room temperature for 14 hours. The desired compound was isolated via preparative thin layer chromatography using a 7:3 Hexanes:Ethyl acetate solvent system. The purified product was characterized by 1H-NMR spectroscopy. 1H-NMR (300 MHz, CD3COCD3): ∂ 1.54-1.75 (15H), 1.93 (m, 12H), 4.65 (2H), 5.09 (3H), 5.53 (1H), 6.40 (1H), 7.11 (3H), 7.81 (1H).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([NH:12][CH2:13][CH2:14][NH2:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([C@H:4]1[NH:12][CH2:13][CH2:14][NH:15][C:3]1=[O:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NCCN[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
(2R)-2-(2-Aminoethylamino)-3-phenylpropionic acid methyl ester (0.67 g; 1.49 mmol) and triethylamine (1 ml) were dissolved in methylene chloride (10 ml) and stirred for 48 hours at room temperature. The reaction mixture was evaporated and the residue was chromatographed on silica (2.5×30 cm) using a 7% solution of ammonia in ethanol/methylene chloride (1:9) as eluent to afford 0.18 g of (3R)-3-benzylpiperazin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5]2.[Br-].[Li+].[CH:22]([Mg]Br)([CH3:24])[CH3:23]>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:22]([CH3:24])[CH3:23])[CH:8]=2)[CH:3]=1
Reactant: CC(C)[Mg]Br
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1ccc2cc(Br)ccc2c1
Temperature: 80 °C
Yield: 33 %

Procedure:
Under an atmospheric argon gas flow, trifluoromethane sulfonic acid-6-bromo-2-naphthyl ester in an amount of 32 g (90 mmol), dichloro (diphenylphosphinoferrocene)palladium in an amount of 3.6 g (5% by mol), lithium bromide in an amount of 7.8 g (90 mmol) and desiccated tetrahydrofuran in an amount of 100 milliliter were placed into three necked-flask equipped with cooling pipe and having a capacity of 500 milliliter, and then, the resultant solution was cooled down to −20° C. After slowly dripping isopropylmagnesiumbromide in an amount of 90 milliliter (90 mmol, 1 mol/liter (tetrahydrofuran)) into the flask, the resultant solution was stirred under heating at the temperature of 80° C. for 4 hours. After the reaction terminated, adding dilute hydrochloric acid in an amount of 100 milliliter into the reacted solution, an organic layer was separated and washed with the use of sodium bicarbonate solution and sodium chloride solution, followed by drying with the use of magnesium sulfate. After removing the solvent by distillation by means of a rotary evaporator, the resultant crude product was refined by means of column chromatography (silicagel, hexane/dichloromethane=90/10), and as a result, 9.4 g of aimed compound (white crystal) was obtained (yield: 33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10](Cl)=[CH:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:7][C:6]=12.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH2:34])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[CH2:32][CH2:33][NH:34][C:10]1[N:5]2[N:4]=[CH:3][C:2]([Br:1])=[C:6]2[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:9]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCN
Reactant: Clc1ccccc1-c1cc(Cl)n2ncc(Br)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCCCC1CCNc1cc(-c2ccccc2Cl)nc2c(Br)cnn12
Temperature: 75 °C
Yield: 78.7 %

Procedure:
3-Bromo-7-chloro-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidine (400 mg, 1.166 mmoles) (prepared as described in Preparative Example 129) was dissolved in anhydrous 1,4-dioxane (5.7 mL). 2-Aminoethylpiperidine-1-carboxylic acid tert-butyl ester (266 mg, 1.166 mmoles) and diisopropyl ethylamine (0.409 mL, 2.33 mmoles) were added and the mixture was heated at 75° C. for 48 h. Additional diisopropyl ethylamine (0.204 mL, 1.166 mmoles) was added and the heating was continued for a total of 58 h. The solution was evaporated to dryness and the residue was chromatographed on a silica gel column (15×5 cm) using dichloromethane followed by 0.3% (10% conc. ammonium hydroxide in methanol)-dichloromethane as the eluant to give 2-{[3-bromo-5-(2-chlorophenyl)pyrazolo[1,5-a]pyrimidin-7-ylamino]ethyl}piperidine-1-carboxylic acid tert-butyl ester (491.1 mg, 79%): FABMS: m/z 534.1 (MH+); HRESIMS: m/z 534.12797 (MH+). Calcd. for C24H30N5O2BrCl: m/z 534.12714; δH (CDCl3) 1.50 (1H, m, CH2), 1.51 (9H, s, COOC(CH3)3), 1.57 (2H, m, CH2), 1.68 (2H, m, CH2), 1.76 (2H, m, CH2), 2.24 (1H, bm, CH2), 2.82/3.40/3.54/4.08/4.51 (5H, m, CH/CH2), 6.34 (1H, s, H6), 7.41 (2H, m, Ar—H), 7.51 (1H, m, Ar—H), 7.76 (1H, m, Ar—H) and 8.08 ppm (1H, s, H2); δC (CDCl3) CH3: 28.5, 28.5, 28.5; CH2: 19.2, 25.5, 29.2, 29.2, 39.2, 67.1; CH: ˜47.4, 87.1, 127.1, 130.1, 130.1, 131.6, 143.9; C: 80.0, 83.0, 132.1, 138.9, 145.7, 146.2, 158.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH:10]=[CH2:11])[CH:3]=1.[CH2:12]([O:15][C:16]1([CH3:45])[CH2:21][CH2:20][N:19]([C:22]2[N:27]3[N:28]=[C:29]([CH2:31]I)[CH:30]=[C:26]3[N:25]=[C:24]([CH3:33])[C:23]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:18][CH2:17]1)[CH:13]=[CH2:14].[H-].[Na+]>CN(C=O)C>[CH2:12]([O:15][C:16]1([CH3:45])[CH2:17][CH2:18][N:19]([C:22]2[N:27]3[N:28]=[C:29]([CH2:31][O:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[CH:10]=[CH2:11])[CH:30]=[C:26]3[N:25]=[C:24]([CH3:33])[C:23]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:20][CH2:21]1)[CH:13]=[CH2:14]
Reactant: C=Cc1cc(F)ccc1CO
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4C=C)nn23)CC1
Yield: 44.7 %

Procedure:
To a mixture of (4-fluoro-2-vinylphenyl)methanol (39.1 mg, 0.257 mmol) in DMF (3 mL) at 0° C. was added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (150 mg, 0.257 mmol) and NaH (10.26 mg, 0.257 mmol). It was then quenched with sat. NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOAc/hexane to isolate (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((4-fluoro-2-vinylbenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (70 mg, 0.115 mmol, 44.8% yield) as an oil. LCMS (M+1)=609.3.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:39])[C@H:22]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:25])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:40]1[CH2:42][C@@H:41]1[CH2:43][O:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:39])[C@H:22]([CH2:32][C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[NH:23][C:24]([CH:26]2[CH2:31][CH2:30][N:29]([CH2:42][C@@H:41]([OH:40])[CH2:43][O:44][C:45]3[CH:54]=[CH:53][CH:52]=[C:51]4[C:46]=3[CH:47]=[CH:48][CH:49]=[N:50]4)[CH2:28][CH2:27]2)=[O:25])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Solvent: CCO
Product: O=C(N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
N-(Piperidine-4-carbonyl)-3-(3-pyridyl)-alanine [4-phenyl- 1-(3-phenyl-propyl)-butyl]-amide (87) (261.8 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 25 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (190 mg) as a white solid. ESMS:MH+ 728.6
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:8]=3[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:10][CH:11]([CH2:12][CH3:13])[C:5]2=[N:4][N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:7]2[N:6]3[C:2]([N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[N:3][N:4]=[C:5]3[CH:11]([CH2:12][CH3:13])[N:10]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:8]=2[CH:20]=1
Reactant: C1CNCCN1
Reactant: CCC1N=C(c2ccccn2)c2cc(C(F)(F)F)ccc2-n2c(Br)nnc21
Product: CCC1N=C(c2ccccn2)c2cc(C(F)(F)F)ccc2-n2c1nnc2N1CCNCC1

Procedure:
In the manner given in Example 1, 1-bromo-8-(trifluoromethyl)-4-ethyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess of piperazine to give 8-(trifluoromethyl)-4-ethyl-1-piperazino-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2=[N:6][N:7]([C:9]3[CH:14]=[C:13]([CH2:15][CH2:16][OH:17])[CH:12]=[C:11]([CH2:18]N(CC)CC)[C:10]=3[OH:24])[N:8]=[C:4]2[CH:3]=1.[Cl:27][C:28]1[CH:46]=[CH:45][C:31]2=[N:32][N:33]([C:35]3[CH:40]=[C:39]([CH2:41][CH2:42][OH:43])[CH:38]=[CH:37][C:36]=3[OH:44])[N:34]=[C:30]2[CH:29]=1.CO.C[O-].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:18]([C:37]1[CH:38]=[C:39]([CH2:41][CH2:42][OH:43])[CH:40]=[C:35]([N:33]2[N:32]=[C:31]3[CH:45]=[CH:46][C:28]([Cl:27])=[CH:29][C:30]3=[N:34]2)[C:36]=1[OH:44])[C:11]1[CH:12]=[C:13]([CH2:15][CH2:16][OH:17])[CH:14]=[C:9]([N:7]2[N:6]=[C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]3=[N:8]2)[C:10]=1[OH:24]
Reactant: OCCc1ccc(O)c(-n2nc3ccc(Cl)cc3n2)c1
Reactant: CCN(CC)Cc1cc(CCO)cc(-n2nc3ccc(Cl)cc3n2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: OCCc1cc(Cc2cc(CCO)cc(-n3nc4ccc(Cl)cc4n3)c2O)c(O)c(-n2nc3ccc(Cl)cc3n2)c1
Yield: 55 %

Procedure:
In 100 ml of xylene were dissolved 37.0 g (93.9 mmols) of crude 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)-6-(N,N-diethylaminomethyl)phenol synthesized in Example 10 and 27.2 g (93.9 mmols) of the purified product of 2-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol synthesized in Example 7. 5 ml of methanol solution of 28% sodium methylate was added, and the mixture was refluxed in a nitrogen stream for 10 hours. The subsequent treatment was carried out in the same manner as in Example 12, giving 30.8 g of 2,2'-methylenebis[6-(5-chloro-2H-benzotriazole-2-yl)-4-(2-hydroxyethyl)phenol] as pale yellow crystals (yield 55.0%, purity 99.0%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])(=[O:13])=[O:12])[CH2:8][C@H:7]1[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:5])C.CO.O.[OH-].[Li+]>O>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[S:11]([CH:9]1[CH2:10][C@@H:6]([C:4]([OH:5])=[O:3])[C@H:7]([CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH2:8]1)(=[O:13])=[O:12]
Reactant: CCOC(=O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)[C@@H]1CC(S(=O)(=O)c2ccccc2Cl)C[C@H]1COc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
To a solution of (1R,2R)-4-(2-Chloro-benzenesulfonyl)-2-(4-chloro-phenoxymethyl)-cyclopentanecarboxylic acid ethyl ester (epimeric mixture, 132 mg) in tetrandrofuran (2.4 mL), methanol (0.6 mL) and water (1.2 mL) was added lithium hydroxide monohydrate (14 mg). The mixture was stirred at 80° C. for 2.5 h then concentrated in vacuo. The residue was dissolved in water and the pH was adjusted to 1 with hydrochloric acid (2N). The precipitate was filtered, washed with water and dried in vacuo to afford the title compound (103 mg, 83%) as a white solid. MS (EI): 446.1 (M+NH4)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:6][C:7]=1[NH:8]CC1C=CC(OC)=CC=1OC)#[N:2].FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:7]1[S:6][C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[C:3]=1[C:1]#[N:2]
Reactant: CCOC(=O)c1sc(NCc2ccc(OC)cc2OC)c(C#N)c1-c1ccc(Cl)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1sc(N)c(C#N)c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.5 %

Procedure:
Ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-[(2,4-dimethoxybenzyl)amino]thiophene-2-carboxylate (4.70 g, 0.00956 mol) was dissolved in dichloromethane (100 mL). Trifluoroacetic acid (25 mL) was added and the solution was stirred at room temperature for 10 minutes. The reaction was concentrated in vacuo, diluted with ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (2.92 g, 90%) as a yellow solid. LCMS: (FA) ES+, 341. 1H NMR (400 MHz, d6-DMSO) δ: 8.17 (s, 2H) 7.75 (d, 1H, J=2.00 Hz), 7.52-7.48 (m, 1H), 7.39 (d, 1H, J=8.28 Hz), 4.05-3.92 (m, 2H), 1.02-0.96 (m, 3H).