Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[C:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[C:34]2[C:30](=[N:31][O:32][N:33]=2)[CH:29]=[CH:28][C:27]=1[S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>>[Cl:25][C:26]1[C:34]2[C:30](=[N:31][O:32][N:33]=2)[CH:29]=[CH:28][C:27]=1[S:35]([N:22]1[CH2:21][CH2:20][CH:19]([C:10]2[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[NH:12][CH:11]=2)[CH2:24][CH2:23]1)(=[O:36])=[O:37]
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3=CCNCC3)c[nH]c12
Reactant: O=S(=O)(Cl)c1ccc2nonc2c1Cl
Solvent: CCN(CC)CC
Product: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCN(S(=O)(=O)c4ccc5nonc5c4Cl)CC3)c[nH]c12

Procedure:
Following the general procedure in example 267, 5-phenyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole-7 carboxamide (32 mg, 0.1 mmol), 4-chloro-2,1,3-benzoxadiazole-5-sulfonyl chloride (38 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (8.0 mg, 15%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:21].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C1COCC1.CO.C(OCC)(=O)C>[Br:21][CH2:19][C:18]([C:7]1[CH:8]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:20]
Reactant: [Br-]
Reactant: CC(=O)c1cc(OCCC(F)(F)F)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(OCCC(F)(F)F)cc(C(=O)CBr)c1

Procedure:
1-[3-tert-Butyl-5-(3,3,3-trifluoropropoxy)phenyl]ethanone (O2.107; 170 mg, 0.59 mmol) was dissolved in a mixture of THF (3 ml) and methanol (3 ml). While stirring, phenyltrimethylammonium tribromide (222 mg, 0.59 mmol) was introduced and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution. After drying over sodium sulfate, the solvent was removed and the residue was purified by flash chromatography (n-heptane:ethyl acetate).
Reaction SMILES: [O:1]=[C:2]([C:8]1[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[S:11][CH:12]=1)[CH2:3][CH2:4][C:5]([OH:7])=O.[NH:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20]>>[S:11]1[CH:12]=[C:8]([C:2]([CH2:3][CH2:4][C:5]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:7])=[O:1])[C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]1=2
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(O)CCC(=O)c1csc2ccccc12
Product: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1csc2ccccc12
Yield: 78 %

Procedure:
The γ-oxo-benzo[b]thiophene-3-butyric acid is coupled to L-proline with 1,1'-carbonylidiimidazole to give 1-[3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline (78%) as a glass. As for Example 1, the preceding compound is reacted with bromine in acetic acid to give 1-[3-bromo-3-(benzo[b]thien-3-ylcarbonyl)propionyl]-L-proline as a glass (97%). Reaction with sodium thioacetate in ethanol gives the product (92%) of the Example as a glass.
Reaction SMILES: [OH:1][CH2:2][C:3]#[CH:4].[O:5]1[CH:10]=[CH:9][CH2:8][CH2:7][CH2:6]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[O:1][CH2:2][C:3]#[CH:4]
Reactant: C#CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 107 %

Procedure:
To a stirred solution of 112 g (2.0 mol.) of 3-hydroxy-1-propyne and 260 g (3.0 mol.) of dihydropyran in 1.20 liters of methylene chloride cooled to 0° C. in an ice bath, is added a solution of 20 mg of para-toluenesulfonic acid in 100 ml of methylene chloride, dropwise. The reaction mixture is stirred at 0° C. for one-half hour, and at ambient temperature for one hour. It is then poured into 200 ml of a 5% solution of sodium bicarbonate, the organic phase is separated, the aqueous phase extracted with 100 ml of methylene chloride, the combined organic phases washed with 100 ml of a solution of brine, dried over sodium sulfate, and evaporated under vacuum (12 mm) at 45° C. to give 300 g of crude product, which is purified by fractional distillation, bp 71°-73° C. (14 mm) to yield 250 g (89%) of a liguid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:10])[C:7]=1[CH2:8]O.S(Br)([Br:13])=O>C(Cl)Cl.CN(C=O)C>[Br:13][CH2:8][C:7]1[C:2]([F:1])=[CH:3][N:4]=[CH:5][C:6]=1[F:10]
Reactant: O=S(Br)Br
Reactant: OCc1c(F)cncc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cncc(F)c1CBr
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(3,5-Difluoro-4-pyridyl)methanol (6.11 g, 42.11 mmol) was dissolved in CH2Cl2 (140 mL). At 0° C. Thionyl bromide (3.589 mL, 46.32 mmol) was added slowly, then 1 drop of DMF was added: the solution turned yellow with gas evolution. The reaction mixture was stirred at rt for 1.5 h. It was quenched with 10 ml water. The pH was made basic (pH=9) with aq NaHCO3. The water layer was extracted 3 times with CH2Cl2. The combined organic layers were washed with brine. The organic phase was dried with Na2SO4, filtrated and the filtrate evaporated. The desired product was obtained as a brown liquid (9.68 g, lacrimator).
Reaction SMILES: [Na].Cl.[CH:3]1([C:6](=[NH:8])[NH2:7])[CH2:5][CH2:4]1.C([O:11][C:12]([CH:14]1[CH2:18][CH2:17][N:16]=[C:15]1OCC)=O)C.Cl>CO.O>[CH:3]1([C:6]2[N:8]=[C:12]([OH:11])[C:14]3[CH2:18][CH2:17][NH:16][C:15]=3[N:7]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1CCN=C1OCC
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: Oc1nc(C2CC2)nc2c1CCN2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.6 %

Procedure:
Sodium (0.417 g, 18.1 mmol) is dissolved in methanol (65 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (2.19 g, 18.1 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo to 30 ml. This free base is added to a solution of sodium (0.834 g, 36.2 mmol) in methanol (130 ml) under a nitrogen atmosphere, at room temperature. 2-ethoxy-4,5-dihydro-3H-pyrrole-3-carboxylic acid ethyl ester (3.4 g, 18.1 mmol) in methanol is added and the mire is stirred at 60° C. overnight. After cooling, the solvent is evaporated and the solid obtained is dissolved in water. The pH is adjusted at 5 with a 5 N HCl solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-ol 48 (1.88 g, 59%) is obtained as a white powder and used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[Cl-:16].[Ca+2].[Cl-]>C(#N)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: [Cl-]
Reactant: O=C(O)CCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Ca+2]
Solvent: CC#N
Product: O=C(O)CCCCCCCCCCCCl

Procedure:
To 12-bromododecanoic acid (1 g) dissolved in acetonitrile (50 ml) was added calcium chloride (2 g) and tetra-n-butylammonium chloride (1.2 g), and the mixture was heated under reflux for 4 hours. The reaction mixture was filtered, concentrated and distributed into ethyl acetate-water, and the ethyl acetate layer was dried over anhydrous sodium sulfate to give 12-chlorododecanoic acid. After a 280 mg portion of 12-chlorododecanoic acid thus obtained, para-nitrophenol (167 mg) and N,N'-dicyclohexylcarbodiimide (245 mg) in N,N-dimethylformamide (DMF) was stirred for 12 hours, precipitates were removed by filtration and DMF was removed by distillation to give an active ester. To the active ester of 12-chlorododecanoic acid dissolved in DMF were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (456 mg) and triethylamine (1.2 ml ), and the mixture was stirred for 12 hours. The reaction mixture was concentrated and subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK132 in the yield of mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])/[CH:5]=[N:6]/[S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8].[CH2:18]([Mg]Br)[CH3:19].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C@H:5]([NH:6][S@:7]([C:9]([CH3:12])([CH3:11])[CH3:10])=[O:8])[CH2:18][CH3:19])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(/C=N/[S@@](=O)C(C)(C)C)cc1F
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To a solution of 66 (3.0 g, 12 mmol) in THF (30 mL) at −78° C. was added a solution of ethylmagnesium bromide in THF (1N, 18 mL, 18 mmol). After stirring for 4 h, the reaction mixture was warmed to 25° C. and stirred at RT overnight. The mixture was treated with NH4Cl, and diluted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (1:1) to afford 1.5 g (45%) of (S)—N—((R)-1-(3-fluoro-4-methoxyphenyl)propyl)-2-methylpropane-2-sulfinamide (68). LCMS (ESI) m/z: 288.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:10]([C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1)#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCC
Reactant: O=Cc1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCC#Cc1cccc(C=O)n1
Yield: 84.3 %

Procedure:
A solution of 6-bromopyridine-2-carboxaldehyde (15.0 g), 1-undecyne (12.9 g), triethylamine (24.5 g), bis(triphenylphosphine)palladium(II)chloride (1.1 g, 2%), and copper(I)iodide (0.15 g, 1%) in dry tetrahydrofuran (60 ml) was heated under nitrogen at 55° C. for 10 hrs. The reaction mixture was filtered, the filter cake was washed with ethyl acetate, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, and the solution was washed with half-saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was flash chromatographed on silica gel, eluting with 0%-2%-ethyl acetate:hexane. The appropriate fractions were collected and evaporated to yield 17.5 g (84.0%) of product.
Reaction SMILES: [CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[Se:8][C:7]=1[C:15]([O:17]CC)=[O:16])[CH3:3].[OH-].[Na+].Cl>CO.O>[CH3:1][N:2]([N:4]=[N:5][C:6]1[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[Se:8][C:7]=1[C:15]([OH:17])=[O:16])[CH3:3]
Reactant: CCOC(=O)c1[se]c(C(C)(C)C)cc1N=NN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)N=Nc1cc(C(C)(C)C)[se]c1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.1 %

Procedure:
To a solution of ethyl 3-[(dimethylamino)diazenyl]-5-(tert-butyl)selenophene-2-carboxylate (400 mg, 1.2 mmol) prepared as described in Example 4 step c) in methanol (10 mL) was added a solution of sodium hydroxide (240 mg, 6.04 mmol) in water (5 mL) and stirred at room temperature (rt) for 16 h. The mixture was diluted with ice cold water and acidified with dil. HCl. The mixture was stirred for 30 min and the precipitated solid was filtered, washed with water and dried. The product was recrystallized from hexane-chloroform to give the product as a pale brown color solid (160 mg, 45%), mp 120-122° C. IR (neat) νmax 2960, 2927, 1713, 1248, 1180, 1110, 1069, 1010, 844, 767 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.23 (1H, s, —COOH), 7.38 (1H, s, H-4), 3.63 (3H, s, —NCH3), 3.23 (3H, s, —NCH3), 1.39 (9H, s, 3×—CH3); 13C NMR (100 MHz, CDCl3): δ 171.7, 164.1, 153.7, 123.2, 115.6, 44.2, 37.2, 36.9, 32.4; LC-MS (positive ion mode): m/z 324, 326 (M+Na)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOC(C)=O.C1CCCCC1>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:20][CH:19]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: Oc1ccc(-c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: Clc1cncc(Oc2ccc(-c3ccccc3)cc2)n1
Yield: 99 %

Procedure:
Using Method DD (reaction time: 20 hours) with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 4-phenyl-phenol (268 mg, 1.49 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:2), the title compound was obtained (376 mg). Yield: 99%. 1H NMR (250 MHz, DMSO-d6) δ 7.40-7.60 (m, 5H, Harom), 7.76 (d, 2H, Harom 3+5, J=7.1 Hz), 7.82 (d, 2H, Harom 2+6, J=8.7 Hz), 8.59 (s, 1H, HPz 5), 8.65 (s, 1H, HPz 3). m/z: 283.1 [(M+H)+, calcd for C16H11ClN2O 282.1].−
Reaction SMILES: CO[C:3]1[CH:12]=[C:11]2[C:6](C[CH2:8][CH2:9][CH:10]2[C:13]#[N:14])=[CH:5][C:4]=1[CH3:15].[CH2:16]([NH2:19])[CH2:17]N.C1(C)C=CC([S:26](O)(=O)=O)=CC=1>>[NH:19]1[CH2:16][CH2:17][N:14]=[C:13]1[CH:10]1[C:11]2[CH:12]=[CH:3][C:4]([CH3:15])=[CH:5][C:6]=2[S:26][CH2:8][CH2:9]1
Reactant: NCCN
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc2c(cc1C)CCCC2C#N
Product: Cc1ccc2c(c1)SCCC2C1=NCCN1

Procedure:
This compound was prepared in a manner analogous to that of Step G of Example 1, by the reaction of 2.0 grams (0.0106 mole) of 7-methyl-2H,3H,4H-benzo[e]thiin-4-carbonitrile (iv) and 6 grams (0.024 mole) of the ethylenediamine salt of p-toluenesulfonic acid (prepared in Step F of Example 1). The reaction product was purified by column chromatography on Grade II alumina (basic-3% water) using a 99:1 mixture of methylene chloride and methanol, respectively, as an eluant. The appropriate fractions of eluate were combined and concentrated under reduced pressure, yielding 1.2 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[O:19][CH3:20].C1COCC1>C(O)C>[F:1][C:2]1[CH:24]=[C:23]([CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[O:19][CH3:20])[NH2:25]
Reactant: COc1cc(C#Cc2ccccn2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(CCc2ccccn2)ccc1Oc1ccc(N)cc1F

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by 2-{[4-(2-fluoro-4-nitrophenoxy)-3-methoxy phenyl]ethynyl}pyridine (0.23 mmol; 84 mg) and THF by ethanol, the title compound was obtained as a clear oil (68%, 53 mg) after purification on preparative TLC (cyclohexane/ethyl acetate: 6/4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[N:9][C:10]=2[CH:11]=1.O[CH2:14][C:15]1[N:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([O:12][CH2:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17]([NH2:19])=[O:18])[CH:3]=1
Reactant: Oc1cc(Br)cc2ncccc12
Reactant: NC(=O)c1cccnc1CO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: NC(=O)c1cccnc1COc1cc(Br)cc2ncccc12
Yield: 45 %

Procedure:
100 mg 7-Bromo-quinolin-5-ol, 77.5 mg of 2-(hydroxymethyl)nicotinamide 3.7, 233.5 mg of triphenylphosphine and 205 mg of Di-tertbutyl-azodicarboxylate (DBAD) were dissolved in 2.5 mL of DCM and 7.5 mL of THF under Argon at room temperature. After 14 h the precipitate was collected and dried. The mother liquor was concentrated and the formed precipitate again collected to yield 72 mg Example 22.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([NH:14][C:15](=[O:24])[C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])=[N:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[N-:25]=[N+:26]=[N-:27].[Na+].Cl.[CH2:30]([NH+](CC)CC)C>CN(C=O)C.C(Cl)Cl>[F:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([F:23])[C:16]=1[C:15]([NH:14][C:12]1[S:13][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]3[N:25]=[N:26][N:27]([CH3:30])[N:2]=3)[CH:4]=2)=[CH:10][N:11]=1)=[O:24]
Reactant: [N-]=[N+]=[N-]
Reactant: CC[NH+](CC)CC
Reactant: N#Cc1cccc(-c2cnc(NC(=O)c3c(F)cccc3F)s2)c1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nnc(-c2cccc(-c3cnc(NC(=O)c4c(F)cccc4F)s3)c2)n1
Temperature: 25 °C
Yield: 33.5 %

Procedure:
A solution of Compound 6 (50 mg, 0.15 mmol), sodium azide (52 mg, 0.75 mmol), triethylammonium hydrochloride (21 mg, 0.15 mmol) in DMF (1 mL) was heated to 110° C. overnight. The mixture was cooled to room temperature, diluted with CH2Cl2. The mixture was eluted through a plug of silica (initially with CH2Cl2, then with 1:9, MeOH: CH2Cl2) provided the crude tetrazole upon solvent removal. Methylation of the crude tetrazole was accomplished by treating the residue with a freshly prepared solution of CH2N2 in ether. The reaction mixture was concentrated under reduced pressure. The residue was purified on silica gel to give Compound 7 (20 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1.[Cl:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[NH2:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][S:9][C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[NH:1][S:28]([C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=1)(=[O:30])=[O:29]
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Product: Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cccc(Cl)c2)c1

Procedure:
Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 3-chloro-benzenesulfonyl chloride.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[CH:29]=3)=[C:26]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[OH-].[Na+]>CC(N(C)C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([O:9][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)[CH:29]=3)=[C:26]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[N:25]=[CH:24]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Cl)c2)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(Oc3ccccc3)c2)CC1
Temperature: 120 °C
Yield: 63.2 %

Procedure:
To a stirring suspension of NaH (120 mg, 3.0 mmol) in DMA (1.3 mL) was added phenol (0.40 g, 4.25 mmol). After the bubbling cease, 1-(1-t-butoxycarbonyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-chloro-4-pyridinyl)imidazole (0.20 g, 0.44 mmol) was added and the resulting solution was heated at 120° C. until no evidence of starting material was seen by mass spectroscopy (1-3 days). To the cooled solution was added 1M NaOH and the mixture was extracted thrice with EtOAc. The combined organic layers were washed with NaCl (sat.), dried over MgSO4, filtered, and evaporated under reduced pressure to give a light yellow solid. The solid was then chromatographed with 50-80% EtOAc/Hex to give the title compound as a white solid (143 mg, 64% yield). ES (+) MS m/e=515 (MH+)
Reaction SMILES: [CH:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)=O.N1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2N=N1.[CH3:25][C@@H:26]1[CH2:31][N:30]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[C@@H:29]([CH3:40])[CH2:28][NH:27]1.C1([Mg]Br)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:25][C@H:26]1[CH2:31][N:30]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[C@H:29]([CH3:40])[CH2:28][N:27]1[C@H:1]([C:3]1[CH:15]=[CH:14][C:6]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Reactant: C[C@@H]1CN(Cc2cccc(F)c2)[C@@H](C)CN1
Reactant: c1ccc2[nH]nnc2c1
Agent: Br[Mg]c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc([C@H](c2ccccc2)N2C[C@@H](C)N(Cc3cccc(F)c3)C[C@@H]2C)cc1
Reaction time: 2 h
Yield: 40.5 %

Procedure:
To a 500 mL three-necked flask was charged 5 g (24.3 mmol) of 4-formyl-N,N-diethylbenzamide (5.8 g @ 86% purity), 4.3 g (36.6 mmol) benzotriazole, 0.05 g (0.24 mmol) 4-toluenesulfonic acid, and 125 mL toluene. The mixture was heated to reflux removing water azeotropicly via a Dean-Stark trap. When water stopped accumulating in the trap, 5.4 g (24.3 mmol) of (2R,5S)-2,5-dimethyl-4-(3-fluorobenzyl)piperazine (IRIX Pharmaceuticals, Florence, S.C., U.S.A.) was added in 2–3 portions, removing water between additions. The reaction was refluxed until the theoretical amount of water was removed (2–3 h), followed by distillation of 100 mL of toluene from the reaction. The remaining solution was cooled below 60° C. Anhydrous tetrahydrofuran (150 mL) was added and the reaction was cooled below 10° C. Phenylmagnesium bromide (1 M in THF, 100 mL, 97.6 mmol) was charged while maintaining the temperature between 0 and 10° C. After stirring for two hours, the reaction was quenched by addition of 100 mL of saturated aqueous ammonium chloride. After phase separation, the aqueous layer was discarded. The organic layer was extracted with 3×75 mL of 1 N HCl. The aqueous layer was washed with 4×74 mL of methyl-tert.-butyl ether. The pH of the aqueous layer was raised to 8–10 with 115 mL 2 N sodium hydroxide. The aqueous layer was extracted with 3×75 mL of methyl-tert.-butyl ether. The organic layer was washed with brine, dried with Na2SO4 and evaporated under vacuum. The resulting solid was dissolved in 3 v/w of hot 2-propanol. Water was charged until a haze was observed. The solution was cooled with stirring to room temperature. The resulting solids were filtered and washed with 1/1 2-propanol-water (50 mL). The filter cake was dried at 40° C. to give 4.8 g (40%) of 4-((alpha-S)-alpha-((2S,5R)-2,5-dimethyl-4-(3-fluorobenzyl)-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[N:17]=1>C(O)C>[Cl:25][C:18]1[N:17]=[C:16]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Nc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccccc1

Procedure:
A mixture of aniline (7.24 g, 78 mmol), triethylamine (13 mL, 93 mmol), and 2,6-dichloro-3-nitropyridine (15 g, 78 mmol) was stirred overnight in 500 mL ethanol at room temperature under nitrogen. The solid that formed was filtered off, washed with water and ethanol, and dried. The solid was purified by column chromatography eluting with 20% ethyl acetate/hexane (8.62 g, 44%).