Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:1]([C:3]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-cyanopiperidine-1-carboxylate (220 mg, 1.05 mmol) and 2-fluoropyridine (0.094 mL, 1.10 mmol) was dissolved in 5.2 mL of THF. The reaction was purged with a stream of nitrogen and cooled to −78° C. To this reaction was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 1.47 mL, 1.47 mmol), which was stirred for 1 h. The reaction was warmed to ambient temperature, stirred for 1 hour, and quenched with a saturated ammonium chloride solution. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and subjected to silica gel chromatography eluting with 0-20% ethyl acetate in hexanes to provide tert-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[CH:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)COCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol (Enantiomer A) and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19]([NH:21][C:22]([CH2:41][OH:42])([CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:38])([CH3:37])[C:34]([CH3:40])([CH3:39])[O:33]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:11]([O:18][C:19]([NH:21][C:22]([CH:41]=[O:42])([CH2:28][CH2:29][CH2:30][CH2:31][B:32]1[O:36][C:35]([CH3:37])([CH3:38])[C:34]([CH3:40])([CH3:39])[O:33]1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C(CO)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)C(C=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
While under an argon atmosphere, a solution of oxalyl chloride (1.56 g, 12.4 mmol, 0.98 mL) in dichloromethane (15 mL) was cooled to −78° C. and treated with dimethyl sulfoxide (1.94 g, 1.8 mL, 24.84 mmol) and stirred for 10 minutes. To this mixture ethyl 2-(benzyloxycarbonylamino)-2-(hydroxymethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.79 g, 6.21 mmol) in anhydrous dichloromethane (15 mL) was added and the mixture was stirred for 30 minutes. The reaction mixture was quenched by adding triethylamine (3.76 g, 5.2 mL, 37.26 mmol) at −78° C. and slowly warming the reaction mixture to room temperature. The mixture was diluted with dichloromethane (25 mL) and washed successively with water (2×25 mL) and saturated aqueous sodium chloride (25 mL). Organic layer was dried over magnesium sulfate, filtered and evaporated to dryness. The resulting residue was purified using a combiflash system (40 g column, eluted with 20-40% ethyl acetate in heptanes) to give ethyl 2-(benzyloxycarbonylamino)-2-formyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.4 g, 86%). 1H NMR (CDCl3) δ: 9.49 (s, 1H), 7.28 (m, 5H), 5.85 (bs, 1H), 5.03 (s, 2H), 4.17, 2.17-2.09 (m, 2H), 1.38-1.28 (m, 4H), 1.25-1.20 (m, 5H), 1.19 (s, 12H), 0.68 (t, J=7.8 Hz, 2H). MS found for C23H34BNO7 m/z [471(M+Na)].
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10].C([Li])CCC.[CH2:16]=[O:17].[Cl-].[NH4+]>O1CCCC1>[CH2:16]([OH:17])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C=O
Reactant: C#CCCCCCCC#C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CCCCCCCC#CCO
Temperature: 0 °C
Yield: 50.4 %

Procedure:
To a solution of 13.42 g of deca-1,9-diyne in 300 ml of absolute tetrahydrofuran were added dropwise over one hour while stirring at -40° C. in an atmosphere of dry nitrogen, 59.4 ml of n-butyllithium solution. After stirring for another hour, during which time the mixture was allowed to warm to 0° C., 6.0 g of paraformaldehyde were added and then the mixture was heated to boil under reflux (TLC: petroleum ether/ether--3:2). When the reaction was finished, a saturated solution of ammonium chloride was added at room temperature. The mixture was extracted several times with ether, the combined extracts were dried over sodium sulfate and then evaporated under vacuum. The oily residue was purified by column chromatography with petroleum ether/ether (3:2) to give 8.27 g of the title compound in the form of a liquid which slowly solidified on storing in a refrigerator.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](O)([CH3:20])[CH3:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[Br:31][CH2:32][C:33]#[N:34].S(=O)(=O)(O)[OH:36]>C(O)(=O)C>[Br:31][CH2:32][C:33]([NH:34][C:18]([C:16]1[CH:15]=[C:14]2[C:9]([CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]2[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=2[Cl:28])=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1)([CH3:19])[CH3:20])=[O:36]
Reactant: O=S(=O)(O)O
Reactant: N#CCBr
Reactant: CC(C)(O)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Solvent: CC(=O)O
Product: CC(C)(NC(=O)CBr)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Reaction time: 8 h

Procedure:
To a stirred suspension of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(1-hydroxy-1-methylethyl)-3,4-dihydroquinazolin-2(1H)-one (460 mg) in acetic acid (0.4 mL) was added bromoacetonitrile (0.1 mL). To this mixture was added concentrated sulfuric acid (0.2 mL) and the resulting solution was allowed to stir overnight. The reaction was quenched by dropwise addition of the mixture to a rapidly stirred mixture of 2N aqueous NaOH and CH2Cl2. Transferred to a separatory funnel, diluted with water and extracted 3× with CH2Cl2. The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated. The product was purified by flash column chromatography on silica gel eluting with 2:1 hexanes/acetone giving 2-bromo-N-{1-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methylethyl}acetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[O:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Clc1ccc([C@H](OC2CCNCC2)c2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCN1CCC(O[C@@H](c2ccc(Cl)cc2)c2ccccn2)CC1
Reaction time: 7 h
Yield: 93.4 %

Procedure:
In 15 ml of acetone was dissolved 1.33 g (4.39 mmol, optical purity: 99.4% e.e.) of (S)-(−)-4-[(4-chlorophenyl) (2-pyridyl)methoxy]piperidine obtained according to Reference example 1, then, 1.03 g (5.28 mmol) of ethyl 4-bromobutanoate and 0.73 g (5.28 mmol) of potassium carbonate were added, and the mixture was refluxed under stirring for 7 hours. Insolubles were filtered off and the filtrate was concentrated under reduced pressure. The resulting slightly yellowish oily product was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol (volume ratio: 30:1) as an eluent. Fractions containing the isolated objective compound were concentrated under reduced pressure to afford 1.71 g of ethyl (S)-4-[4-[(4-chlorophenyl)(2-pyridyl)methoxy]piperidino]-butanoate as an oily product (Yield: 93.4%, optical purity: 99.4% e.e.). [α]D25 −6.60° (c=1, MeOH)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[NH:32][CH:31]=1>C1COCC1.C(OCC)(=O)C>[N:30]1([C:2]2[N:7]=[C:6]([NH:8][CH:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)[C:5]([N+:15]([O-:17])=[O:16])=[C:4]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:3]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[CH:31]1
Reactant: O=[N+]([O-])c1c(NC2CCOCC2)nc(Cl)nc1-c1ccccc1
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(NC2CCOCC2)nc(-n2cnc3ccccc32)nc1-c1ccccc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 38.4 %

Procedure:
To 100 mg (0.3 mmol) of 2-chloro-5-nitro-6-phenyl-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-amine in 5 mL of THF was added potassium carbonate (213 mg, 1.54 mmol, 5.1 equiv.), followed by benzimidazole (106 mg, 0.9 mmol, 3 equiv.) and the reaction mixture was stirred at 70° C. After 2.5 h, heating was discontinued; the reaction mixture was diluted with 70 mL of ethyl acetate, was washed with water and dried (anhydrous MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, elution with 4/1 hexanes/ethyl acetate) to give the desired product (48 mg, 38% yield). LC-MS: tR=7.35 min, MS (EI) m/z 417.2 (MH)+.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7](O)=[CH:6][C:5]=2[O:4]1.[CH:13]1C=CN(S(C2C=CSC=2CBr)(=O)=O)C=1>CN(C=O)C.O>[CH3:7][CH2:6][CH2:5][CH2:10][CH2:9][CH3:8].[CH3:10][CH2:5][O:4][C:3]([CH3:13])=[O:11]
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=S(=O)(c1ccsc1CBr)n1cccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Sodium hydride (100 mg, 5 mmole) was added to a stirred solution of 3,4-methylenedioxyphenol (0.607 g, 4.5 mmol) in DMF (dry, 5 ml) at 0° C. under a nitrogen atmosphere with stirring. The reaction mixture was permitted to attain room temp and stirring continued for 1 hr. The reaction mixture was cooled to 0° C. and N-[(2-bromomethyl)thiophene-3-sulfonyl]pyrrole was added. Stirring was continued at ambient temperature for 16 hr. The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (2×50 ml) and washed with 1N NaOH (2×25 ml) to remove phenol derivative. The mixture was dried over MgSO4 and concentrated resulting in N-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}pyrrole, which was recrystallized using hexane/EtOAc (1.0 g, 92% yield).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:16])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[N:6]=1.[N:17]1[CH:22]=NC=N[CH:18]=1.[CH2:23]([C:25]1C=[CH:30][CH:29]=[CH:28][C:26]=1N)[CH3:24]>C(O)C>[CH2:29]([C:28]1[CH:26]=[CH:25][CH:23]=[CH:24][C:18]=1[NH:17][CH:22]=[C:3]1[C:2]([CH3:1])=[N:6][N:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)[C:4]1=[O:16])[CH3:30]
Reactant: CCc1ccccc1N
Reactant: c1ncncn1
Reactant: CC1=NN(c2ccc([N+](=O)[O-])cc2)C(=O)C1
Solvent: CCO
Product: CCc1ccccc1NC=C1C(=O)N(c2ccc([N+](=O)[O-])cc2)N=C1C

Procedure:
1 g of 5-methyl-2-(4-nitrophenyl)-2,4-dihydro-3-pyrazolone, 190 mg of 1,3,5-triazine and 0.74 ml of 2-ethylaniline are heated under reflux in 50 ml of ethanol for 4 days. The solvent is evaporated off in vacuo, and the crude reaction product obtained in this way is purified by chromatography on silica gel with a solvent mixture consisting of dichloromethane and methanol mixed in the ratio of 97:3 as eluent.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[N:4][CH:3]=[N:2]1.[CH:9]([NH:12][C:13]([C@H:15]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]2[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=[C:24](OCCOC)[CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])[CH3:10]>>[N:1]1([CH2:6][CH2:7][O:8][C:24]2[CH:23]=[C:22]([NH:21][C@@H:18]3[CH2:19][CH2:20][C@H:15]([C:13]([NH:12][CH:9]([CH3:11])[CH3:10])=[O:14])[CH2:16][CH2:17]3)[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][N:25]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Reactant: OCCn1cncn1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCn3cncn3)ncc2[N+](=O)[O-])CC1

Procedure:
Intermediate cis-4-(2-(2-(1H-1,2,4-triazol-1-yl)ethoxy)-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide was prepared in 2 steps from 2-(1H-1,2,4-triazol-1-yl)ethanol using a procedure analogous to that used to prepare cis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (104 mg).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[CH:6][CH:5]=1>C(O)(=O)C.ClCCl>[Br:1][C:12]1[S:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=2)=[C:14]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Temperature: 2 °C
Reaction time: 0.75 h

Procedure:
Bromine (1 ml) was added dropwise to a solution of 2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (5.3 g) in acetic acid (53 ml) and dichloromethane (53 ml) at 2° C. The mixture was stirred at 2° C. for 45 minutes and concentrated to dryness. The residue was collected and washed with water and ethanol to give dark green crystals of 5-bromo-2-(4-fluorophenyl)-3-(4-nitrophenyl)thiophene (6.5 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH3:13])[C:7]([CH3:15])([CH3:14])[CH:6]1[NH2:16])#[N:2].[H][H].N>CO.[Co]>[NH2:2][CH2:1][CH2:3][CH2:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([CH3:13])[C:7]([CH3:15])([CH3:14])[CH:6]1[NH2:16]
Reactant: [H][H]
Reactant: CN1C(C)(C)CC(CCC#N)C(N)C1(C)C
Agent: [Co]
Agent: N
Solvent: CO
Product: CN1C(C)(C)CC(CCCN)C(N)C1(C)C

Procedure:
100 parts of 4-(β-cyanoethyl)-amino-1,2,2,6,6-pentamethylpiperidine were dissolved in 500 parts of methanol and hydrogenated at a hydrogen pressure of 80 to 100 bar and a temperature of 80° to 100° C. with the addition of 150 parts of liquid ammonia and 25 parts of Raney cobalt until uptake of hydrogen ceased. The catalyst was removed by filtration and the filtrate was fractionated under vacuum. 95 parts of 4-(γ-aminopropyl)-amino-1,2,2,6,6-pentamethylpiperidine, boiling point 110° to 112° C./0.1 torr, were obtained.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:11][C:12]3[C:20]([I:21])=[CH:19][C:15]4[O:16][CH2:17][O:18][C:14]=4[CH:13]=3)[NH:8]2)=[C:4]([NH2:22])[N:3]=1.Br[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:22][C:4]1[N:3]=[C:2]([F:1])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:11][C:12]1[C:20]([I:21])=[CH:19][C:15]3[O:16][CH2:17][O:18][C:14]=3[CH:13]=1)[N:8]2[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: Nc1nc(F)nc2[nH]c(Cc3cc4c(cc3I)OCO4)nc12
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(Cc2cc3c(cc2I)OCO3)nc2c(N)nc(F)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.9 %

Procedure:
To a solution of 2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine (3.3 g, 8 mmol) in DMF (50 mL) was added t-butyl (3-bromopropyl)carbamate (9.6 g, 40 mmol) and Cs2CO3 (5.26 g, 16 mmol). The resulting mixture was stirred at room temperature for 1 day. The reaction mixture was condensed and purified by flash chromatography to yield t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate as white solid (3.1 g, 66%). The solution of t-butyl (3-(6-amino-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-9-yl)propyl)carbamate (1.9 g, 3.3 mmol) in the mixture of TFA/CH2Cl2 (10 mL/2 mL) was stirred at room temperature for 2 hrs. The reaction mixture was condensed, purified by flash chromatography to yield 9-(3-aminopropyl)-2-fluoro-8-((6-iodobenzo[d][1,3]dioxol-5-yl)methyl)-9H-purin-6-amine as yellow solid (1.4 g, 89%). 1H NMR (600 MHz, CDCl3/MeOH-d4): δ 7.28 (s, 1H), 6.70 (s, 1H), 5.98 (s, 2H), 4.21 (s, 2H), 4.13 (t, J=7.1 Hz, 2H), 2.67 (t, J=6.8 Hz, 2H), 1.89 (m, 2H); 13C NMR (150 MHz, CDCl3/MeOH-d4): δ 160.8, 159.4, 157.8, 153.7, 152.1, 150.4, 149.4, 132.4, 120.1, 117.2, 111.3, 103.4, 89.8, 41.7, 40.4, 39.3, 33.6; HRMS (ESI) m/z [M+H]+ calcd. for C16H17IFN6O2, 471.0436. found 471.0442.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[N:10][C:9]([C:12]([O:14]CC)=[O:13])=[N:8]1.[Li+].[OH-].CO.Cl>C1COCC1>[C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH:11]=[N:10][C:9]([C:12]([OH:14])=[O:13])=[N:8]1
Reactant: CCOC(=O)c1ncn(-c2ccccc2C)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1-n1cnc(C(=O)O)n1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a solution of ethyl 1-(o-tolyl)-1,2,4-triazole-3-carboxylate (400 mg, 1.7 mmol) in 3 mL THF was added 4 M LiOH (2 mL, 8 mmol) followed by 3 mL of MeOH. The reaction mixture was stirred at 50° C. for 5 minutes, after which the pH was adjusted to 4 with the addition of conc. HCl. After extraction, drying (MgSO4), filtration and drying under reduced pressure, 43 mg of residue was recovered (12%) and used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][CH:6]([CH2:10][CH3:11])[C:7]([OH:9])=[O:8].[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31](O)[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[CH2:37]2)=[CH:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]1[CH2:32][C@H:31]([O:8][C:7](=[O:9])[CH:6]([O:5][C:4]2[CH:12]=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=2)[CH2:10][CH3:11])[C@H:30]2[C:25]([CH:26]=[CH:27][C@H:28]([CH3:51])[C@@H:29]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:45])[CH3:46])[CH2:37]2)=[CH:24]1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16]
Reactant: CCC(Oc1cccc(C)c1)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CCC(Oc1cccc(C)c1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 98.5 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 0.71 g of (2RS)-2-(3-methylphenoxy)butyric acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.30 g of the title compound as a colorless foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[C:15](OCC)=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8]1.O.O1CCCC1.O>C(OCC)C>[N:7]1([C:12]2[CH:13]=[C:14]([CH2:15][OH:16])[CH:20]=[CH:21][CH:22]=2)[CH:11]=[CH:10][CH:9]=[CH:8]1
Reactant: CCOC(=O)c1cccc(-n2cccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: OCc1cccc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.7 %

Procedure:
To a stirred mixture of 4.8 grams of lithium aluminum hydride in 150 ml of dry diethyl ether was added dropwise 23.2 grams (0.108 mole) of ethyl 3-(pyrrol-1-yl)benzoate in 160 ml of dry diethyl ether. The complete addition required 45 minutes. After this time the reaction mixture was heated under reflux for 45 minutes then allowed to cool to ambient temperature where it stood for 16 hours. The excess lithium aluminum hydride was decomposed by the careful addition of 20 ml of 50% (v/v) water-tetrahydrofuran. The addition required 20 minutes as the reaction mixture temperature was kept below 25° C. The reaction mixture was poured into 300 ml of water and the diethyl ether layer separated. The aqueous layer was extracted with three portions of 200 ml each of diethyl ether. The combined ether layers were washed with water and dried with magnesium sulfate. The mixture was filtered and the filtrate concentrated under reduced pressure to give 20.9 grams of 3-(pyrrol- 1-yl)phenylmethanol; mp 64°-67° C. The ir spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4].[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+]>>[CH2:1]([S:6]([CH2:9][CH2:10][CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=[O:8])=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCS(=O)(=O)CCCCl
Reactant: C1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCS(=O)(=O)CCCN1CCCCC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
Heat 3-chloropropyl isopentyl sulfone (700 mg, 3.29 mmol) and piperidine (1.7 g, 20 mmol) at 125° C. for 45 minutes. Cool to room temperature, treat with 5N sodium hydroxide, extract with ethyl acetate (3×25 mL), and dry (MgSO4). Concentrate in vacuo to yield 850 mg orange oil. Purify by silica gel chromatography (50% ethyl acetate/methanol) to yield 500 mg of the title compound as a pale yellow oil.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.CN1CCOCC1.[NH2:42][OH:43].Cl.[OH-].[K+]>C1COCC1.CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6](=[O:5])[NH:42][OH:43])(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
{Carboxymethyl-[4-(4-bromo-phenoxy)-benzenesulphonyl]-amino}-acetic acid (4b) (500 mg, 1.30 mmol) was dissolved in dry THF (10 mL). ECF (100 μL, 1.12 mmol), and NMM (120 μL, 1.12 mmol) were added and stirred for 40 min at 0° C. NH2OH×HCl (90 mg, 1.30 mmol) and KOH (73 mg, 1.30 mmol) were dissolved in dry MeOH (10 mL) and stirred at 0° C. for 30 min. The solids were filtered off, and the THF solution was added dropwise to the methanol filtrate and stirred for 2 h at 0° C. The reaction mixture was filtered, the solvent evaporated, and the residue dissolved in H2O (25 mL). After adjusting the pH to 1-2, the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4, evaporated in vacuo, and co-evaporated with EtOAc (3×3 mL) to yield the pure product as light-pink solid. Yield: 267 mg, 0.67 mmol, 52%. 1H-NMR (DMSO-d6): δ 7.91 (dd, 2H, 3JHH=9.0 Hz, 4JHF=5.1 Hz, ArH), 7.42 (t, 2H, 3JHH=9.0 Hz, 3JHF=9.0 Hz, ArH), 4.07 (s, 4H, 2×CH2CO2H). ESI-MS calcd for C16H15FN2O7S 398.06 [M-H]−, obsd 399.10