Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:19]=[C:18]([Cl:20])[C:15]([C:16]#[N:17])=[C:14]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[N:13]=2)=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:20][C:18]1[C:15]([C:16]#[N:17])=[C:14]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:23][CH:22]=2)[N:13]=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:3])[CH3:2])=[CH:11][CH:10]=2)[CH:19]=1
Reactant: CC(=O)Cl
Reactant: N#Cc1c(Cl)cc(-c2ccc(N)cc2)nc1-c1ccc(Oc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2cc(Cl)c(C#N)c(-c3ccc(Oc4ccccc4)cc3)n2)cc1
Reaction time: 1.5 h
Yield: 46.8 %

Procedure:
Acetyl chloride (0.013 mL, 0.181 mmol) was added to a suspension of 6-(4-aminophenyl)-4-chloro-2-(4-phenoxyphenyl)nicotinonitrile (48 mg, 0.121 mmol, from Step 3 of Example 199) and Hunig's base (0.084 mL, 0.483 mmol) in dichloromethane (1 mL) at room temperature. After 90 min at room temperature, additional acetyl chloride (0.05 mL) was added. After additional 23 h, the reaction was stopped and the mixture purified by silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, to give N-(4-(4-chloro-5-cyano-6-(4-phenoxyphenyl)pyridin-2-yl)phenyl)acetamide as yellow solid (24.9 mg, 47% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (2H, δ, J=8.78 Hz), 8.00-8.03 (2H, m), 7.79 (1H, s), 7.68 (2H, δ, J=8.53 Hz), 7.35-7.44 (3H, m), 7.19 (1H, t, J=7.40 Hz), 7.08-7.15 (4H, m), 2.23 (3H, s); MS (ES+) m/z: 440 (M+H); LC retention time: 4.668 min (analytical HPLC Method A). Unreacted starting material was also recovered (13.7 mg).
Reaction SMILES: [S:1]1(=[O:20])(=[O:19])[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C@@H:3]([C:9]([O:11]CC2C=CC=CC=2)=[O:10])[CH2:2]1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[S:1]1(=[O:20])(=[O:19])[C@@H:5]2[CH2:6][C:7](=[O:8])[N:4]2[C@@H:3]([C:9]([OH:11])=[O:10])[CH2:2]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)[C@H]1CS(=O)(=O)[C@@H]2CC(=O)N12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)[C@H]1CS(=O)(=O)[C@@H]2CC(=O)N12

Procedure:
To a solution of 131 mg of benzyl (3S, 5R)-penam-3-carboxylate 1,1-dioxide in a mixture of 15 ml of methanol and 10 ml of ethyl acetate was added 100 mg of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen at atmospheric pressure until hydrogen uptake ceased. At this point, the reaction mixture was filtered and the solvent was removed by evaporation in vacuo. This afforded 106 mg of the title compound [alpha]D25 =203 (CH3OH; C=1). The NMR spectrum (60 MHz; D2O) showed absorptions at 4.85 (m, 1H), 4.82 (m, 1H), 3.85 (m, 2H) and 3.43 (m, 2H) ppm. The IR spectrum (film) showed absorptions at 1760 and 1730 cm-1.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[S:22])[NH2:21])=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH:24]([C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][C:26]([OH:28])=[O:27]>C(OCC)(=O)C>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:22][C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:21]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CC(Br)C(=O)c1ccccc1
Reactant: CC(C)(C)c1csc(-c2cc3cc(CC(N)=S)ccc3o2)n1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(-c5ccccc5)c(CC(=O)O)s4)ccc3o2)n1
Yield: 6.6 %

Procedure:
A solution of 4-tert-butyl-2-[5-(thiocarbamoylmethyl)-benzofuran-2-yl]thiazole (740 mg) and 3-bromo-4-oxo-4-phenylbutanoic acid (600 mg) in ethyl acetate (8.0 ml) was heated under reflux for 13.5 hours. After being cooled, the resulting precipitates were collected by filtration and washed with ethyl acetate. The precipitates were dissolved in ethyl acetate, washed with aqueous sodium hydrogen carbonate solution and brine, dried over magnesium sulfate and concentrated under reduced pressure to give a mixture. The mixture was subjected to column chromatography on silica gel and eluted with a mixture of chloroform, methanol and ethyl acetate (20:1:1 to 20:1:2). The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[(5-carboxymethyl-4-phenylthiazol-2-yl)methyl]benzofuran-2-yl}thiazole (72 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([O:39][CH3:40])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:18]2)=[O:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([S:26]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]([O:39][CH3:40])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:18]2)=[O:16])[CH2:9]1
Reactant: COc1ccc(S(=O)(=O)N2CC(C(=O)NC3CCCN(C(=O)OC(C)(C)C)C3)c3ccccc32)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CC(C(=O)NC3CCCNC3)c3ccccc32)c2ccccc12
Yield: 77.8 %

Procedure:
To a solution of (A) (500 mg, 0.99 mmol) in dichloromethane (12 cm3) was added, with stirring, trifluoroacetic acid (2 cm3). The reaction was then allowed to stir at room temperature for 3 h, after which the solvents were removed by evaporation under reduced pressure. Dichloromethane (40 cm3) was added to the residue and the mixture was then washed with saturated aqueous sodium bicarbonate solution (30 cm3) followed by water (30 cm3) and saturated sodium chloride solution (50 cm3). The resulting organic mixture was then dried over sodium sulfate and evaporated under reduced pressure to afford the title compound as a pale yellow solid (310 mg, 0.77 mmol; 77%). Positive ion ESI (M+H)+ 466.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:16].Br[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC(C)([O-])C.[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:15]([NH:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:21][CH2:20]1)=[O:16]
Reactant: COc1ccc(C(=O)NCC2CCNCC2)cc1OCCc1ccc(Cl)cc1Cl
Reactant: Brc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NCC2CCN(c3ccccc3)CC2)cc1OCCc1ccc(Cl)cc1Cl

Procedure:
A mixture of 100 mg (0.2 mmol) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide, 50 mg (0.32 mmol) Bromobenzene, 70 mg sodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min. Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd2(dba)3 were added under argon and the mixture refluxed overnight. The residue was taken up in 3 ml saturated NaHCO3 solution and filtered through a chem elut® cartridge by elution with ethyl acetate. Subsequent removal of the solvent under reduced pressure and purification by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.5% TFA) the fractions containing the product were evaporated and lyophilised.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[O:9]([C:11]1[C:16]([Br:17])=[CH:15][CH:14]=[C:13]([O:18][CH3:19])[N:12]=1)[CH3:10].Cl[P:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C1COCC1>[CH3:10][O:9][C:11]1[C:16]([Br:17])=[C:15]([P:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[C:13]([O:18][CH3:19])[N:12]=1
Reactant: COc1ccc(Br)c(OC)n1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(P(c2ccccc2)c2ccccc2)c(Br)c(OC)n1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
To a magnetically stirred solution of 4.0 mL of approximatly 2.0M LDA solution (in hexane) (7.98 mmol) was added a solution of 2,6-dimethoxyl-3-bromopyridine (3.14 g, 6.14 mmol) in 10 mL of THF at -78° C. over a period 20 minutes while the internal temperature was kept below -78° C. To the resulting red-brown suspension was added a solution of chlorodiphenylphosphine (1.20 mL, 6.75 mmol) in the 10 mL of THF at -78° C. The reaction mixture was allowed to warm to ambient temperature overnight and was poured into 20 mL water. The organic product was extracted with dichloromethane (3×20 mL). The combined extract was dried with anhydrous magnesium sulfate and was concentrated in vaccuo to give a crude product which was recrystallized in methanol to give 2.34 g of pure product (95% theoretical yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][CH2:6][CH:7]1[O:20][C:10]2=[C:11]3[C:16](=[CH:17][CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]3>O>[OH:5][CH2:6][C:7]1([N+:1]([O-:4])=[O:2])[O:20][C:10]2=[C:11]3[C:16](=[CH:17][CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]3
Reactant: O=[N+]([O-])O
Reactant: O=c1ccc2c3c(ccc2[nH]1)CC(CO)O3
Solvent: O
Product: O=c1ccc2c3c(ccc2[nH]1)CC(CO)([N+](=O)[O-])O3
Reaction time: 0.33 h
Yield: 75.3 %

Procedure:
70% Nitric acid (10 ml, d=1.42) was added dropwise to 2-hydroxymethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one while cooling on ice, and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was poured into ice and water (200 ml), and precipitated crystals were collected by filtration. After drying with air, recrystallization was performed using methanol to obtain 3.0 g of 2-hydroxymethyl-nitro-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one as yellowish brown prisms (75.3%, mp. 215°-218° C.).
Reaction SMILES: [CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[O:33][CH2:32][CH:31]5[CH2:34][NH:35][CH2:36][CH2:37][N:30]5[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:39]>>[CH2:1]([N:8]1[C:16]([CH3:17])=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:19]=[C:20]([CH:28]4[O:33][CH2:32][CH:31]5[CH2:34][N:35]([CH3:39])[CH2:36][CH2:37][N:30]5[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c2ccc(-c3cc(C4CN5CCNCC5CO4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Reactant: CI
Product: Cc1c2ccc(-c3cc(C4CN5CCN(C)CC5CO4)n4ncnc(N)c34)cc2nn1Cc1ccccc1
Yield: 27 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 103 and using 5-(2-benzyl-3-methyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine and iodomethane as the starting materials, 18 mg (27%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) 7.91 (s, 1 H), 7.75 (d, 1 H), 7.52 (s, 1 H), 7.34-7.19 (m, 5 H), 7.06 (dd, 1H), 6.72 (s, 1H), 5.63 (s, 2H), 5.14-5.10 (m, 1H), 3.73 (dd, 1H), 3.37-3.30 (m, 1H), 2.93 (dd; 1H), 2.75-2.63 (m, 4H), 2.61 (s, 3H), 2.41 (t, 1H), 2.25-2.06 (m, 3H), 1.57 (s, 3H); LC-MS [M+H]+=509, RT=0.28 min.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[Br-:10].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[C:3]([CH2:1][CH3:2])[CH:8]=1
Reactant: [Br-]
Reactant: CCc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(Br)ccc1O
Reaction time: 0.33 h

Procedure:
15 g (123 mmol) of 2-ethylphenol are dissolved in 150 ml of chloroform. 59 g (123 mmol) of tetrabutylammonium tribromide are added in portions of 10 g, and the reaction medium is stirred for 20 minutes. The medium is then poured into a saturated sodium thiosulphate solution, and then the pH is adjusted to 7. The mixture is extracted with dichloromethane. After drying and concentration, the residue obtained is purified by chromatography on a silica column (eluent ethyl acetate 10/heptane 90). A yellow oil is obtained (m=24.5 g, y=99%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=O)[CH2:5][CH2:4]1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:49][CH:48]([C:50]([N:52]2[CH2:58][CH2:57][CH2:56][N:55]([CH:59]3[CH2:62][CH2:61][CH2:60]3)[CH2:54][CH2:53]2)=[O:51])[CH2:47]1>CN(C=O)C.C(Cl)Cl.C(Cl)Cl>[CH:59]1([N:55]2[CH2:56][CH2:57][CH2:58][N:52]([C:50]([CH:48]3[CH2:47][N:46]([C:9]([CH:6]4[CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:8][CH2:7]4)=[O:11])[CH2:49]3)=[O:51])[CH2:53][CH2:54]2)[CH2:62][CH2:61][CH2:60]1
Reactant: O=C(C1CNC1)N1CCCN(C2CCC2)CC1
Reactant: COC1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC1CCC(C(=O)N2CC(C(=O)N3CCCN(C4CCC4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11 %

Procedure:
To a stirred solution of 4-methoxycyclohexane carboxylic acid (20 mg, 0.13 mmol) in DMF/DCM (1:1) (2 ml) was added HOBt (38 mg, 0.28 mmol) and HBTU (96 mg, 0.25 mmol) and the reaction mixture stirred for 15 mins at RT. 1-(Azetidin-3-ylcarbonyl)-4-cyclobutyl-1,4-diazepane (30 mg, 0.13 mmol) in DCM (1 ml) was added and the reaction mixture stirred at RT for 16 hrs. Upon completion, the reaction mixture was evaporated at reduced pressure and purified by silica gel FCC (using DCM/MeOH/NH3; 95:5:0.5 to 90:10:1 as eluent) to give the title compound as colourless oil and as a 1:1 mixture of diastereoisomers by 1H NMR spectroscopy (5.2 mg, 11% yield).
Reaction SMILES: Cl.[CH3:2][C:3]12[CH2:8][C:7]1([CH3:9])[CH2:6][NH:5][CH2:4]2.Cl[CH2:11][C:12]#[C:13][CH2:14][OH:15].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:2][C:3]12[CH2:8][C:7]1([CH3:9])[CH2:6][N:5]([CH2:11][C:12]#[C:13][CH2:14][OH:15])[CH2:4]2
Reactant: CC12CNCC1(C)C2
Reactant: OCC#CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC12CN(CC#CCO)CC1(C)C2
Temperature: 25 °C

Procedure:
To a stirring solution of 1,5-dimethyl-3-azabicyclo[3.1.0]hexane hydrochloride (0.3 gm, 2 mmol) in chloroform (50 ml), 1-chloro-4-hydroxy-2-butyne (0.11 gm, 1 mmol), followed by triethylamine (0.3 gm, 3 mmol) were added. The reaction mixture was refluxed for 3 hours and then allowed to cool to room temperature. The solvents were evaporated in vacuo. The residual oil was purified by column chromatography using silicagel (100-200 mesh), eluting the compound with 50-50 ethyl acetate-hexane mixture.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH:11]=O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:18][CH:17]=1)([O-:15])=[O:14].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.CC(O)=O>[CH3:1][C:2]1[CH:9]=[C:8]([CH2:10][CH2:11][N:27]2[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][C:19]3[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=3)[CH2:25][CH2:26]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(CC=O)ccc1C#N
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(CCN2CCN(CCc3ccc([N+](=O)[O-])cc3)CC2)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-4-(2-oxoethyl)benzonitrile (130 mg, 0.8 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (190 mg, 0.8 mmol) in 25 mL of dry methanol were added 2 drop of HOAc and then stirred at room temperature for 1 hr. Then NaBH(OAc)3 (380 mg, 1.8 mmol) was added an the then the mixture was stirred overnight. Concentrated and the residue was purified via prep-TLC to give 2-Methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.15 (d, J=8.6 Hz, 2H), 7.36˜7.53 (m, 3H), 7.12 (t, J=9.4 Hz, 2H), 2.65˜2.97 (m, 16H), 2.52 (s, 3H). MS m/e: 379 (M+1)+. (0.19 μM)
Reaction SMILES: O.NN.[CH:4]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([C:14](=O)[C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:6][CH2:5]1.[OH-].[K+].O>C(OCC)C>[CH:4]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: O=C(O)C(=O)c1ccc(SC2CC2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)Cc1ccc(SC2CC2)cc1
Temperature: -78 °C
Yield: 84.5 %

Procedure:
Hydrazine hydrate (4.77 mL, 153.4 mmol) was placed in a three neck flask fitted with an overhead stirring rod and a reflux condenser and cooled in a dry ice acetone bath at −78° C. After the solution reached −50° C. the bath was removed and (4-cyclopropylsulfanyl-phenyl)-oxo-acetic acid (3.41 g, 15.34 mmol) was added in one portion. The temperature increased due to an exotherm and it was then heated in an oil bath to 80° C. After the reaction was at 80° C. it was treated with potassium hydroxide (593 mg, 9.20 mmol) and stirred vigorously. When the reaction returned to 80° C. a second portion of potassium hydroxide (593 mg, 9.20 mmol) was added and allowed to cool back to 80° C. This cycle was repeated two more times adding potassium hydroxide (593 mg, 9.20 mmol) each time. The reaction was then heated at 100° C. for 16 h over which time the reaction became a homogenous clear yellow solution. It was then cooled to 25° C. and water (3 mL) added to the reaction. It was then transferred to a separatory funnel and another portion of water (3 mL) was added and diethyl ether (10 mL). The layers were separated and the aqueous layer separated into a flask. The organic layer was then extracted with water (5 mL) and this aqueous layer combined with the first. To the aqueous layers was then added heptane (5 mL) and stirred vigorously. This solution was cooled to 0° C. in an ice bath and was treated dropwise with concentrated hydrochloric acid (˜7 mL) over 30 min until the aqueous layer was at pH=2 keeping the temperature of the solution below 50° C. during the addition process and it turned cloudy. It was then allowed to cool to 25° C. and stirred for 3 h. It was then filtered to remove the solids and the solids were washed with 1N aqueous hydrochloric acid (1.5 mL), water (2×1.5 mL), heptane (5 mL) and 1:1 heptane:diethyl ether (5 mL) and the solid was then dried in a vacuum oven to afford (4-cyclopropylsulfanyl-phenyl)-acetic acid (2.70 g, 85%) as a yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[NH:12][N:11]=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:12]2[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][N:10]=[N:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(Cc2nnn[nH]2)cc1
Product: c1ccc(Cc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared from 5-benzyl-1H-tetrazole and triphenylmethyl-chloride.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[CH:17]=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>>[C:8]([N:15]1[CH2:21][CH2:20][CH2:19][C@H:16]1[C:17]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18])([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: Cl[Mg]C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C1CCCC1

Procedure:
22.5 ml (45 mmol) 2 M cyclopentylmagnesium chloride (diethyl ether) and 3.0 g (15 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of crude product 3.37 g. The product was purified with a silica column using 0–4% methanol in dichloromethane as eluent. Yield 3.10 g (11.5 mmol, 77%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 3.12 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.3 g (4.9 mmol, 42%).
Reaction SMILES: [CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18](Cl)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([N:3]1[C:15]2[C:14]([O:16][CH3:17])=[CH:13][CH:12]=[C:11]([S:18]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:2]
Reactant: COc1ccc(S(=O)(=O)Cl)c2c3ccccc3n(C=O)c12
Reactant: COc1ccc(N)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c3c2c2ccccc2n3C=O)cc1
Yield: 65 %

Procedure:
Intermediate 63 (0.2 g, 0.62 mM) was dissolved in 40 ml of chloroform. To it was added p-anisidine (0.21 g, 1.66 mM), 0.19 g triethylamine and the reaction was refluxed for 18 hrs. Solvent was evaporated and the residue was extracted in ethyl acetate. The organic layer was washed with 10% HCl solution, brine and then dried over anhydrous Na2SO4. It was then evaporated to obtain the crude residue which was then purified over silica gel column using ethylacetate-hexane system to obtain the desired compound as beige solid with a yield of 65% (0.16 g); mp 190-192° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([OH:33])[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:32])[CH3:31]>CC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([O:33][CH2:2][C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[O:13][CH3:14])[CH:25]=[N:26][C:27]=1[O:28][CH2:29][CH:30]([CH3:31])[CH3:32]
Reactant: CC(C)COc1ncc(O)cc1Cl
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(COc2cnc(OCC(C)C)c(Cl)c2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of methyl 4-(bromomethyl)-3-methoxybenzoate (250 mg, 0.965 mmol) in acetone (20.0 mL) were added potassium carbonate (267 mg, 1.93 mmol) and 5-chloro-6-isobutoxypyridin-3-ol (Preparation 1, 195 mg, 0.965 mmol) and the reaction mixture was heated at reflux for 16 hours, then allowed to cool to room temperature. The solvent was removed in vacuo to yield a yellow solid, which was partitioned between EtOAc (30.0 mL) and water (50.0 mL). The aqueous was further extracted with EtOAc (2×30 mL). The combined organics were washed with sodium hydroxide solution (1 M, 30 mL) then brine (50 mL), dried over sodium sulfate and the solvent was removed in vacuo to yield the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[OH:20]O.O>C(O)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][C:10]([CH3:19])([C:15]([F:18])([F:16])[F:17])[C:11]([F:12])([F:13])[F:14])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1ccc(SCC(C)(C(F)(F)F)C(F)(F)F)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)CC(C)(C(F)(F)F)C(F)(F)F)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
To 1-methyl-4-(3,3,3-trifluoro-2-methyl-2-trifluoromethylpropylthio)benzene (4.5 g, 14.9 mmol) in acetic acid (15 mL) at ambient temperature, add with stirring aqueous hydrogen peroxide (15 mL, 30% in water) and stir for 1 h. Dilute the reaction with water, extract three times with EtOAc, dry over anhydrous Na2SO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give the desired intermediate as a colorless oil (4.125 g, 88%).