Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[F:39])[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[F:39][C:33]1[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=1[C:30]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=2[CH3:7])[CH:31]=1
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(F)cc2F)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc(F)cc3F)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μL of N,N-dimethylformamide and 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 49 mg of tert-butyl 2-amino-4-(2,4-difluorophenyl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 4-(2,4-difluorophenyl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19](S(C3C=CC([N+]([O-])=O)=CC=3[N+]([O-])=O)(=O)=O)[C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:13]=2)=[CH:4][N:3]=1.C(N)CC>C(Cl)Cl.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][C@@H:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)[CH:13]=2)=[CH:4][N:3]=1
Reactant: CNC(=O)c1cc(-c2cccc(CN([C@H]3CCc4ccccc43)S(=O)(=O)c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])c2)cnc1N
Solvent: CCCN
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(-c2cccc(CN[C@H]3CCc4ccccc43)c2)cnc1N

Procedure:
2-Amino-5-(3-{[[(2,4-dinitrophenyl)sulfonyl][(1S)-2,3-dihydro-1H-inden-1-yl]amino}methyl}phenyl]-N-methylpyridine-3-carboxamide was treated with excess n-propylamine (4 eq) in CH2Cl2 (150 mL). The mixture was diluted with additional ethyl acetate (200 mL). The mixture was subsequently washed with aqueous saturated sodium carbonate (3×30 mL) and brine (3×30 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by preparative HPLC (acetonitrile/water) gave desired product (5.8 g). The compound was converted to the hydrochloride salt using 4 M solution HCl in dioxane: 1H NMR (400 MHz; DMSO-d6): 9.9 (br s, NH); 9.02 (s, 1H); 8.9 (s, 1H); 8.6 (s, 1H); 8.35 (br s, NH); 8.2 (s, 1H); 7.8 (d, 2H); 7.75 (m, 2H); 7.37 (m, 2H1); 7.29 (m, 1H); 4.85 (m, 1H); 4.25 (m, 2H); 3.4 (m, 1H); 2.9 (m, 1H); 2.80 (d, 3H); 2.43 (m, 1H); 2.4 (m, 1H); MS (EI) for C23H24N4O HCl: 374 (MH+).
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.[C:19]([C:23]1[CH:28]=[C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C:26]([CH3:37])=[CH:25][C:24]=1[SH:38])([CH3:22])([CH3:21])[CH3:20]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:19]([C:23]1[CH:28]=[C:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[C:26]([CH3:37])=[CH:25][C:24]=1[S:38][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: Cc1cc(S)c(C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
A mixture of tosyl bromide (1.82 g, 7.76 mmol), Et3N (1.08 mL, 7.76 mmol), and CCl4 (15 mL) was cooled to 0° C. and treated with a solution of 2-tert-butyl-4-(tert-butyl-dimethyl-silanyloxy)-5-methyl-benzenethiol (prepared in Example III; 1.94 mmol) in CCl4 (15 mL) via addition funnel over a period of 45 minutes. The mixture was then allowed to warm to room temperature where it was stirred for 4 days. The mixture was diluted with CH2Cl2 and quenched with saturated NH4Cl. The layers were separated, the organic layer dried (Na2SO4) and the solvent removed in vacuo. The residue was submitted to column chromatography (3:1 hexanes:CH2Cl2 to 1:1 hexanes:CH2 Cl2) to provide the title compound. 1H NMR (CDCl3) δ 0.0 (s, 6 H), 0.78 (s, 9 H), 0.97 (s, 9 H), 1.84 (s, 3 H), 2.18 (s, 3 H), 6.60 (s, 1 H), 6.94-7.02 (m, 4 H), 7.25 (s, 1 H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].[Cl:9][CH2:10][CH2:11][S:12]([CH2:15][CH2:16][C:17](Cl)=[O:18])(=[O:14])=[O:13].N1C=CC=CC=1.C(Cl)(Cl)Cl>O1CCCC1>[C:1]([O:5][CH2:6][CH2:7][O:8][C:17](=[O:18])[CH2:16][CH2:15][S:12]([CH2:11][CH2:10][Cl:9])(=[O:14])=[O:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCO
Reactant: O=C(Cl)CCS(=O)(=O)CCCl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=CC(=O)OCCOC(=O)CCS(=O)(=O)CCCl
Temperature: 5 °C
Reaction time: 1.75 h
Yield: 88.6 %

Procedure:
A mixture of 600 ml of tetrahydrofuran, 45.8 g of hydroxyethyl acrylate, and 72 g of 3-(2-chloroethylsulfonyl)propionic acid chloride was placed in a reactor, and while maintaining the temperature at 5° C. or lower by cooling by ice water, a solution containing 31.2 g of pyridine dissolved in 100 ml of tetrahydrofuran was added dropwise thereto over a period of 1.75 hours. The resulting mixture was further stirred for 2 hours at room temperature. At the end of the time, the reaction mixture was poured into 2.5 liters of ice water, and extraction was performed four times with 300 ml of chloroform. The organic layer thus extracted was dried over sodium sulfate and concentrated to provide 87 g of 2-[3-(chloroethylsulfonyl)propionyloxy]ethyl acrylate as pale yellow waxy product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]=[CH:7][C:8]([O:10][CH3:11])=[O:9].C(N(CC)CC)C.[C:25]1([C:31]2[N:32]([CH2:43][C:44](Cl)=[O:45])[C:33](=[O:42])[O:34][C:35]=2[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][N:6]1[C:44](=[O:45])[C@H:43]([N:32]2[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:34][C:33]2=[O:42])[C@@H:7]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C=NCc1ccc(OC)cc1OC
Reactant: O=C(Cl)Cn1c(-c2ccccc2)c(-c2ccccc2)oc1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1[C@@H](n2c(-c3ccccc3)c(-c3ccccc3)oc2=O)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 1 h

Procedure:
Methyl N-(2,4-dimethoxybenzyl)iminoacetate (1.43 g) is dissolved in 13 ml of dry methylene chloride and 1 ml of triethylamine and cooled in an ice bath. A solution of 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid chloride (2.0 g, 6.4 mmole) in 10 ml of methylene chloride is added over a 10 minute period. After one hour, the mixture is washed with water and 5% aqueous sodium bicarbonate then dried and evaporated to give a red oil which is chromatographed on silica gel to give methyl cis-1-(2,4-dimethoxybenzyl)-3-(4,5-diphenyl-2-oxo-4-oxazolin-3-yl)-4-oxoazetidine-2-carboxylate.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10](O)[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:45]>C(Cl)Cl>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:10]([Cl:45])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OC1C=CC(c2ccccc2)(c2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: ClC1C=CC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4,4-diphenyl-2-cyclopenten-1-ol (0.30 g), and triphenylphosphine (0.43 g) in carbon tetrachloride (3 ml) was refluxed for 8 hours and cooled. To the mixture was added n-hexane (5 ml), and the mixture was stirred for 10 minutes at room temperature. The insoluble material was filtered off and the filtrate was condensed under reduced pressure. The residue was dissolved in methylene chloride, and to the solution was added silica gel (1 g). After being stirred for 10 minutes, silica gel was filtered off and the filtrate was evaporated in vacuo to give 4,4-diphenyl-2-cyclopentenyl chloride (0.30 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[C:34]([O:41][CH3:42])(=[O:40])[CH2:35][CH2:36][C:37]([O-])=[O:38].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:37](=[O:38])[CH2:36][CH2:35][C:34]([O:41][CH3:42])=[O:40])[CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C[C@@H]2CCCNC2)CC1
Reactant: COC(=O)CCC(=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC(=O)N1CCC[C@@H](CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
To a solution of N-(3,4-dichlorophenyl)-4-[(3R)-piperidin-3-ylmethyl]piperazine-1-carboxamide (200 mg), N,N-di-isopropylethylamine (0.19 mL) and monomethyl succinate (79 mg) in dimethylformamide (5 mL) was added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-Tetramethyluronium Hexafluoro-Phosphate. The solution was stirred at room temperature overnight and then loaded directly onto an SCX-2 column and eluted with methanol then 7M NH3 in methanol. The basic fraction was concentrated at reduced pressure and the residue was purified by silica column chromatography, eluting with a gradient of 0 to 10% methanol in dichloromethane to give the title compound as a white foam (252 mg, 96%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=O.[CH3:14][NH:15][C:16]([NH2:18])=[S:17]>C(O)C>[CH3:14][NH:15][C:16]1[S:17][CH:2]=[C:3]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)[N:18]=1
Reactant: CNC(N)=S
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: CNc1nc(-c2ccc(C(=O)O)cc2)cs1
Temperature: 0 °C
Yield: 103.7 %

Procedure:
To 25 ml of ethanol were added 4-(2-bromoacetyl)benzoic acid (486 mg, 2 mmole) and N-methyl thiourea (180 mg, 2 mmole). The reaction mixture was refluxed for 3 hr and the TLC showed the disappearing of the starting materials and the formation of a fluorescent product. The reaction was cooled on ice. The product was collected on filtration and washed with ethanol pre-cooled to 0° C. twice (2×3 ml), followed by diethyl ether. After drying, 486 mg product was obtained. 1H NMR (DMSO-d6, 400 MHz) δ 7.97 (2H, d), 7.89 (2H, d), 7.32 (1H, s), 2.96 (3H, s).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=O)=[CH:15]3)=[N:9][CH:10]=1)(=[O:4])=[O:3].Cl.C[N:33](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([NH2:33])=[O:30])=[CH:15]3)=[N:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)nc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)nc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 27.7 %

Procedure:
A mixture of 5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (2.5 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.2 g), 1-hydroxybenzotriazole (1.6 g), and N,N-dimethylformamide (25 mL) was stirred at 50° C. for 30 min. The reaction mixture was cooled to room temperature, 10% aqueous ammonia (4 mL) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, water was added to the residue, and ethyl acetate-tetrahydrofuran was added. The precipitated solid was collected by filtration to give the title compound (0.69 g) as a pale-yellow solid. The filtrate was concentrated under reduced pressure to evaporate the organic solvent. The precipitate was collected by filtration to give the title compound (0.72 g) as a pale-yellow solid (total yield 1.41 g, 64%).
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:5].CN(C=O)C.O1CCOCC1.[Br:23][CH2:24][C:25](Br)=[O:26]>O>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:25](=[O:26])[CH2:24][Br:23])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(Br)CBr
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: O=C(CBr)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of 2-amino-5-chlorobenzoic acid (10 g, 0.06 mol), anhydrous DMF (30 mL) and dioxane (30 mL) was cooled to 0° C. in a 250 mL 3- necked flask, fitted with a magnetic stirrer, thermometer and additional funnel. Bromoacetyl bromide (11.8 g, 5 mL, 100 mol %) was added dropwise over a 20 min period, keeping the internal temperature between 0° C. to 1° C. After the addition was completed, the solution was allowed to warm to room temperature and stirring was continued overnight at rt. The reaction mixture was cooled in an ice-bath, stirred for 30 min and diluted with water (80 mL). The resulting light yellow precipitate was filtered, washed with water, and dried in vacuum oven (20 h, 40°-45° C.), to afford 11.4 g (67%) of the title compound, mp 210°-212° C. (decomp.); 1H NMR (CD3OD) δ 8.58 (d, 1H, J=9.2), 8.03 (d, 1H, J=2.8), 7.55 (dd, 1H, J=2.4, J=6.4), 4.11 (s, 2H); 13C NMR (CD3OD) δ 196.94, 169.69, 140.49, 134.86, 131.94, 129.49, 122.87, 119.47, 30.04; MS (EI, m/z) 293 (M+).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C@@H:18]3[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1.C(O)(=O)C.O=[C:29]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30]1.[Na]>ClCCl>[O:23]=[C:15]1[N:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH:29]3[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30]3)[CH2:13][CH2:12]2)[C@@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]2[NH:16]1
Reactant: O=C1N[C@@H]2CCCC[C@H]2N1C1CCNCC1
Reactant: CCOC(=O)N1CCC(=O)C1
Agent: [Na]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(N2CCC(N3C(=O)N[C@@H]4CCCC[C@H]43)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (3aR,7aR)-1-piperidin-4-yloctahydro-2H-benzimidazol-2-one TFA salt (400 mg, 1.24 mmol) in dichloromethane (10 mL) was added acetic acid (0.35 mL 6.12 mmol)-ethyl 3-oxopyrrolidine-1-carboxylate (0.35 mL 2.23 mmol). Sodium triacetoxyoborohydride (0.8 g, 3.77 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with ice water, then diluted with dichloromethane (200 mL) and was washed successively with 1N NaOH (10 mL), water (10 mL) and brine. The solvent was removed under reduced pressure and the residue was purified by high pH prep LCMS (acetonitrile/water) to provide the mixture of two diastereoisomers (260 mg 58%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:22]=[C:21]([Br:23])[CH:20]=[C:17]([CH:18]=O)[C:16]=1[OH:24]>>[Br:14][C:15]1[C:16]([OH:24])=[C:17]([CH:20]=[C:21]([Br:23])[CH:22]=1)[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cc(Br)cc(Br)c1O
Product: O=c1cc(N2CCN(Cc3cc(Br)cc(Br)c3O)CC2)nc[nH]1

Procedure:
6-[4-(3,5-Dibromo-2-hydroxy-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,5-dibromosalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.62-2.66 (m, 4H), 3.48 (s, 1H), 3.58-3.65 (m, 4H), 3.72 (s, 2H), 5.40 (s, 1H), 7.07 (s, 1H), 7.58 (s, 1H), 7.84 (s, 1H), 11.90 (br s, 1H). Mass spectrum (ES) MH+=445.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I:12][C:13]1[CH:18]=[CH:17][C:16](O)=[C:15]([CH3:20])[CH:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC([O-])=O>C1COCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][C:15]=1[CH3:20]
Reactant: Cc1cc(I)ccc1O
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(I)ccc1O[C@H](CCCl)c1ccccc1
Yield: 70.4 %

Procedure:
The compound [R]-(+)-1-chloro-3-phenyl-3-(4-iodo-2-methylphenoxy)propane (Compound 5) was prepared in the same manner as for the preparation of Compound 2 in Example 1, but using [S]-3-chloro-1-phenylpropanol (1.0 g, 5.88 mmol), 4-iodo-2-methylphenol (1.38 g, 5.88 mmol), triphenylphosphine (1.54 g, 5.88 mmol), and ethyl azodicarboxylate (0.93 mL, 1.04 g, 5.88 mmol) in THF (15 mL) at room temperature for 15 hours. Workup and purification gave 1.60 g (70%) of Compound 5 as a thick pale yellow liquid: [απ25D +14.02 (c 7.7, CHCL3); 1H NMR (CDCl3, 250 MHz) δ 7.41-7.20 (m, 7H), 6.39 (d, J=8.8 Hz, 1H), 5.34 (dd, J=4.4, 8.8 Hz, 1H), 3.81-3 72 (m, 1H), 3.63-3.55 (m, 1H), 2.55-2.41 (m, 1H), 2.31-2.16 (m, 1H), 2.7 (s, 3H); FTIR (neat) 3080, 3020, 2970, 2915, 1585, 1485(s), 1450, 1390, 1360, 1290, 1245(s), 1180, 1130 cm-1. Anal. C17H20INO: C,H.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=O.P(Cl)(Cl)([Cl:14])=O.[S:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>CCOCC>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4]([Cl:14])=[C:21]3[CH2:22][S:17][CH2:18][CH2:19][C:20]3=[N:1][C:2]=2[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCSCC1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CCOCC
Product: Clc1ccc2c(Cl)c3c(nc2c1)CCSC3
Yield: 64 %

Procedure:
To a slurry of 14.8 g (0.0863 mol) of 2-amino-4-chlorobenzoic acid and 150 ml of phosphorous oxychloride is added dropwise 10 g (0.086 mol) of tetrahydrothiopyran-4-one. The mixture is stirred at reflux for 3 hours and then concentrated in vacuo. The residue is dissolved in methylene chloride and edded slowly to an ice-NH4OH mixture. The mixture is stirred for 1/2 hour and extracted with methylene chloride. The combined extracts are washed with water, dried over Na2SO4, and concentrated in vacuo to yield a dark solid. Trituration with ether furnishes 15 g (64%) of title compound: m.p. 112°-115° C.; IR (KBr) 1605, 1480, and 1415 cm-1 ; NMR (CDCl3) δ 8.08-8.02 (m, 2H), 7.58-7.52 (m, 1H), B 4.08 (s, 2H), 3.44 (t, 2H), and 3.09 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[O:5][CH2:6][C:7]#[N:8].O.O.[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:11]=1)[O:5][CH2:6][C:7]#[N:8]
Reactant: N#CCOc1cc(Cl)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CCOc1cc(N)cc(Cl)c1
Temperature: 70 °C
Yield: 62.5 %

Procedure:
A warm solution of 8.23 g of (3-chloro-5-nitro-phenoxy)-acetonitrile in 150 ml of ethyl acetate was treated with 34.9 g of tin (II) chloride dihydrate and the solution was heated at 70° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, basified with saturated sodium bicarbonate solution, extracted twice with ethyl acetate, dried (MgSO4), and evaporated to dryness. The residue was purified by silica gel chromatography using ethyl acetate/hexane (35:65) as solvent and obtained 4.42 g of (3-amino-5-chloro-phenoxy)-acetonitrile as a cream solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=1.C([Sn]([C:41]#[N:42])(CCCC)CCCC)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:14][Si:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][O:10][CH2:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]1[N:5]2[N:25]=[CH:26][CH:27]=[C:4]2[N:3]=[C:2]([C:41]#[N:42])[CH:7]=1
Reactant: CCCC[Sn](C#N)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(Cl)nc2ccnn12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C#N)nc2ccnn12
Temperature: 150 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
5-chloro-N,N-bis((2-(trimethyl silyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (1.5 g, 3.5 mmol), tributyltin cyanide (1.7 g, 5.3 mmol), tetrakis(triphenylphosphine) palladium (0.8 g, 0.7 mmol), bis(tri-t-butylphosphine) palladium (0.4 g, 0.7 mmol) were charged in a pressure tube. The tube was evacuated and charged with argon for three cycles. Dioxane (20 ml) was added, and the tube was capped and heated at 150° C. with stirring for one hour. After cooling, the mixture was diluted with EtOAc (100 ml) and washed with brine (1×20 ml), dried over MgSO4. Solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-35%) gave desired product, 7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidine-5-carbonitrile (1.3 g, 90%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-])=O)=[CH:5][C:4]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[N:3]1.[Cl-].[NH4+]>[Zn].C1COCC1.CO>[CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:10]2[O:11][CH:12]=[N:13][N:14]=2)=[N:3]1
Reactant: Cn1nc(-c2nnco2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nc(-c2nnco2)cc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 31 %

Procedure:
To a mixture of 2-(1-methyl-5-nitro-1H-pyrazol-3-yl)-1,3,4-oxadiazole (2.56 g, 13.1 mmol), ammonium chloride (4.91 g, 92 mmol) in a 1:1 solution of THF/MeOH (82.6 mL) at about 0° C. was added zinc dust (6.0 g, 92 mmol) portionwise. The reaction was stirred for about 10 min at about 0° C. The ice bath was removed and the reaction stirred at ambient temperature for about 16 h. The reaction mixture was filtered through a pad of Celite® rinsing with MeOH (50 mL). The filtrate was concentrated under reduced pressure. The material was partitioned between DCM (50 mL) and water (10 mL). The aqueous layer was back extracted with DCM (2×50 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The aqueous layer was acidified using 1 N HCl to about pH 3 and back extracted with DCM (50 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The organic layer batches were combined to afford 1-methyl-3-(1,3,4-oxadiazol-2-yl)-1H-pyrazol-5-amine (0.67 g, 4.06 mmol, 31%, which was used without further purification). LC-MS (Table 1, Method g) Rt=0.59 min, m/z 166 (M+H)+.