Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH3:21][O:22][C:23]([CH2:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)=[O:24]>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[NH:30][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][C:23]([O:22][CH3:21])=[O:24])=[CH:32][CH:31]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: COC(=O)Cc1ccc(NC(=O)CC2CCc3cc(Br)cc4[nH]c(=O)c(=O)n2c34)cc1
Yield: 81.2 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and p-methoxycarbonylmethylaniline (215 mg, 1.3 mmol) to give 395 mg of the title compound (81%): mp 262° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ10.02 (s, 1H), 7.50 (d, 2H, J=8.3 Hz), 7.23 (bs, 1H), 7.18 (d, 2H, J=8.3 Hz), 7.17 (bs, 1H), 5.17~5.26 (m, 1H), 3.61~3.62 (m, 5H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.84 (dm, 1H, J=17.1 Hz),2.56~2.66 (m, 2H), 2.11 (dm, 1H, J=13.5 Hz), 1.76~1.94 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]([O:16][CH2:17][CH2:18][OH:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][CH2:17][CH2:18][O:19][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OCCOCc1ccccc1
Product: Brc1ccc(OCCOCc2ccccc2)nc1

Procedure:
Prepared from 2,5-dibromopyridine and benzyloxy-2-ethanol by the method of Example 10 (b).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:28])[C@@H:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:12][O:13][C:14](=[O:28])[C@@H:15]1[CH2:19][C@H:18]([O:20][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:17][N:16]1[C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
4-Dimethylaminopyridine (2.28 g) and p-toluenesulfonyl chloride (2.66 g) were added to a cold (0° C.) stirred solution of N-tert-butoxycarbonyl-cis-4-hydroxy-L-proline methyl ester (J, 2.76 g) in dichloromethane (50 mL). After stirring at room temperature for 16 hr, the solvent was removed in vacuo. The residue was diluted with ethyl acetate, and washed with 0.5 M saturated citric acid, water, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo to give the title compound (3.10 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.35-1.52 (m, 9H), 2.30-2.53 (m, 2H), 2.46 (s, 3H), 3.51-3.78 (m, 2H), 3.68-3.69 (s, 3H), 4.30-4.56 (m, 1H), 5.00-5.09 (m, 1H), 7.32-7.38 (m, 1H), and 7.74-7.79 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][N:12]2[CH:13]=1.C1C(=O)N([I:24])C(=O)C1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:16][CH2:15][CH2:14][N:12]2[C:13]=1[I:24]
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1ccc(-c2cn3c(n2)CCC3)c(F)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(-c2nc3n(c2I)CCC3)c(F)c1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a stirred solution of 2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole (93.5 g, 425 mmol) in DMF (550 mL), NIS (105 g, 467 mmol) was added portionwise over about 1 h, maintaining the temperature at about 20-25° C. with an ice-water bath. After the final addition, the reaction suspension was stirred for about 2 h. After a total of about 3 h from the start of addition of the NIS, the reaction mixture was poured into ice water (4 L) and was stirred at about 15-20° C. for about 15 min before the addition of a 10% solution of Na2S2O3 (500 mL). The resulting solution was stirred for about 1 h. The tan colored solid was collected by vacuum filtration, washed with water (5×200 mL), and dried overnight at room temperature. The solid was stirred with ether (300 mL), filtered, and washed with additional portions of ether (3×30 mL). This ether trituration process was repeated before the solid was dried in a vacuum oven at about 50-60° C. to give the title compound as a powdery solid (91.4 g, 52%): LC/MS (Table 1, Method h) Rt=1.40 min; MS m/z: 347.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:17]Cl>>[Cl:17][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2nsc3ccccc23)cc1
Reactant: ClCl
Product: ClCc1ccc(-c2nsc3ccccc23)cc1
Yield: 80.2 %

Procedure:
225 g of 3-(4'-methylphenyl)-1,2-benzisothiazole are heated to 170° C. in a stirred apparatus and 100 g of chlorine are passed in over 2 hours whilst irradiating the mixture with a UV lamp. The end point of the reaction is determined by gas chromatography (disappearance of the starting material). The reaction mixture is then cooled and the product is filtered off and recrystallized from methanol. 208 g of 3-(4-chloromethylphenyl)-1,2-benzisothiazole, melting at 86°-89° C., are obtained; this yield corresponds to 80% of theory.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14](O)=[O:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2cccc(Br)c2)nc1CC(=O)O
Solvent: C1CCOC1
Product: Cc1oc(-c2cccc(Br)c2)nc1CCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
A solution of 2-(3-bromophenyl)-5-methyl-4-oxazoleacetic acid (39.1 g, 0.13 mol) in dry THF (175 mL) was treated dropwise with borane-THF complex (227 mL of a 1.0 M solution in THF, 1.3 mol) over 2 h (reaction temperature to 35° C.). After stirring 2 h at room temperature under N2, the reaction was quenched with slow addition of methanol (60 mL) and stirred overnight at room temperature. The reaction was diluted with 1 N NaOH (50 mL) and extracted with CH2Cl2 (2×200 mL). The organic layer was washed with H2O (3×100 mL), dried (MgSO4), and the solvent removed in vacuo to give 38.7 g of crude product that was recrystallized from toluene (200 mL, wash solid with cold hexanes) to give 26.9 g (72%) of 2-(3-bromophenyl)-5-methyl-4-oxazoleethanol as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6][Br:15]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 120.8 %

Procedure:
To a mitre of 3-methoxy-4-nitrobenzyl alcohol (3.00 g) and carbon tetrabromide (8.15 g) in dichloromethane (60 mL) was added triphenylphosphine (5.16 g) under ice-water cooling, and the mixture was stirred for an hour at ambient temperature. After evaporation of the solvent, the residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (5:1) to give 3-methoxy-4-nitrobenzyl bromide as pale yellow powders (4.87 g).
Reaction SMILES: OB(O)[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22](Br)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([N:16]1[C:25]2[C:20](=[CH:21][C:22]([C:3]3[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)=[CH:23][CH:24]=2)[C@H:19]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C@@H:17]1[CH2:34][CH2:35][CH3:36])(=[O:15])[CH3:14]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CCC[C@H]1C[C@@H](Nc2ccccc2)c2cc(Br)ccc2N1C(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCC[C@H]1C[C@@H](Nc2ccccc2)c2cc(-c3ccc(C(=O)O)cc3)ccc2N1C(C)=O
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
A mixture of 4-(dihydroxyboranyl)benzoic acid (25.7 mg, 0.155 mmol), (cis)-1-acetyl-6-bromo-N-phenyl-2-propyl-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see intermediate 86) (40 mg, 0.103 mmol), tetrakis(triphenylphosphine)palladium(0) (11.93 mg, 10.33 μmol) and potassium carbonate (42.8 mg, 0.310 mmol) in 1,4-dioxane (1 mL) and water (0.5 mL) was stirred at 130° C. for 15 min under microwave irradiation then cooled to room temperature and concentrated in vacuo. Purification of the residue by MDAP (modifier:formic acid) gave 4-[(cis)-1-acetyl-4-(phenylamino)-2-propyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoic acid (19 mg, 0.044 mmol, 43%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[CH:9]=[C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(=O)CC>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:16][C:3]1[C:2]([Cl:1])=[C:14]([Cl:15])[C:6]2[S:7][C:8]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:9][C:5]=2[CH:4]=1)[CH3:23]
Reactant: CC(C)Cc1cc2cc(O)c(Cl)c(Cl)c2s1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a mixture of 10 g of 6,7-dichloro-5-hydroxy-2-isobutylbenzo[b]thiophene and 200 ml 2-butanone is added a mixture of 6.9 g of ethyl bromoacetate in 50 ml of 2-butanone and by 6.6 g of potassium carbonate and 3.4 ml sieve-dried dimethylformamide. The reaction mixture is stirred at 95°-100° for 2 hrs, allowed to cool and filtered. To the filtrate is added 100 ml of water and 100 ml of ether. The organic layers are combined, washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give a solid. Recrystallization from ethyl ether and hexane gives 12 g of ethyl[(6,7-dichloro-2-isobutylbenzo[b]-thien-5-yl)oxy]acetate, mp 75°-76°.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: O=[N+]([O-])c1cc(Cl)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc([N+](=O)[O-])c3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2 g, 8 mmol, 1 eq.) and 4-chloro-2-nitropyridine (2.53 g, 16 mmol, 2 eq.) in 50 ml of DMF was added cesium carbonate (7.8 g, 24 mmol, 3 eq.). The reaction was stirred at room temperature overnight. It was then quenched by water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography on silica gel (DCM/methanol=19:1 to 4:1) to give desired product as light yellow oil. MS (ESI) m/z=743 [2M−H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2ccc(F)nc2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, white solid (55 mg, 69%), MS (ISP) m/z=321.5 [(M+H)+], mp 264.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 6-fluoro-pyridin-3-ylboronic acid (45.8 mg, 0.325 mmol).
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].[NH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O.P(Cl)(Cl)Cl>>[CH2:7]([CH2:6][NH2:5])[CH2:8][C:9]([P:1]([OH:4])([OH:3])=[O:2])([P:1]([OH:4])([OH:3])=[O:2])[OH:11]
Reactant: NCCCC(=O)O
Reactant: OP(O)O
Solvent: ClP(Cl)Cl
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 70 °C

Procedure:
The mixture of 5 eq. phosphorous acid, 4-aminobutyric acid and morpholine. HCl is melted together until uniform solution is formed. The reaction mixture is cooled to about 70° C. and 2 eq. of PCl3 are carefully added. The mixture is heated for about 5.5 hours before the reaction mixture is hydrolyzed in aqueous acid at about 80° C. and alendronate is isolated from an ethanolic solution.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:17]12[NH:24][CH:21]([CH2:22][CH2:23]1)[CH2:20][C:19](=[O:25])[CH2:18]2>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:24]2[CH:17]3[CH2:23][CH2:22][CH:21]2[CH2:20][C:19](=[O:25])[CH2:18]3)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=C1CC2CCC(C1)N2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CC2CCC(C1)N2Cc1ccc(Br)cc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A stirred solution of 1-bromo-4-bromomethylbenzene (0.39 g, 1.56 mmol), triethylamine (0.45 mL, 3.20 mmol) and 8-azabicyclo[3.2.1]octan-3-one (0.33 mL, 2.32 mmol) in THF (10 mL) was heated under reflux for 5 h. The reaction mixture was allowed to cool to ambient temperature and the solid removed by filtration. The filtrate was concentrated under reduced pressure to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-100% DCM in ethyl acetate) to afford the title compound as an off-white solid (400 mg, 90%). 1H NMR (CDCl3, 300 MHz): 7.48-7.43 (m, 2H), 7.32-7.28 (m, 2H), 3.69 (s, 2H), 3.49-3.43 (m, 2H), 2.66 (dd, J=16.0, 4.3 Hz, 2H), 2.26-2.17 (m, 2H), 2.14-2.06 (m, 2H), 1.66-1.56 (s, 2H). LCMS (Method B): RT=1.86 min, M+H+=294/296.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:21]>O>[Br:21][C:11]1[CH:13]=[CH:14][C:8]([N:6]2[CH2:5][CH2:4][O:3][CH:2]([CH3:1])[CH2:7]2)=[CH:9][CH:10]=1
Reactant: Br
Reactant: CC1CN(c2ccc(N)cc2)CCO1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CN(c2ccc(Br)cc2)CCO1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-methylmorpholino)aniline (7.21 g, 37.5 mmol) in 100 mL HBr in water (40%), a solution of NaNO2 (2.59 g, 37.5 mmol) in 15 mL water was added slowly at −10° C.˜0° C. The mixture was stirred for 30 minutes and was added dropwise to a solution of CuBr (2.96 g, 20.6 mmol) in 30 mL HBr in water (40%). The resulting mixture was stirred and heated at 60° C. for 2 hours. Then the reaction solution was adjusted by 2N NaOH solution to pH>7. Extracted by EA, the combined organic phase was washed with brine, dried and concentrated to give crude product as black oil. MS (m/z): 256 (M+H)+; 258 (M+3)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=[O:12])=[C:5]2[CH2:16][CH2:17][CH2:18][O:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.[C:30]1([CH2:36]/[CH:37]=[CH:38]/B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Li+].[OH-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:20]1([O:19][CH2:18][CH2:17][CH2:16][C:5]2[C:9]3[C:8](=[CH:4][CH:3]=[C:2](/[CH:38]=[CH:37]/[CH2:36][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:10]=3)[NH:7][C:6]=2[C:11]([OH:13])=[O:12])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1CCCOc1cccc2ccccc12
Reactant: OB(O)/C=C/Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)c1[nH]c2ccc(/C=C/Cc3ccccc3)cc2c1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 11C (45.2 mg), (E)-3-phenylprop-1-enylboronic acid (21.1 mg), bis(triphenylphosphine)palladium(II) dichloride (catalytic), and 2M LiOH (0.3 mL) in 7/2/3 dimethoxyethane/ethanol/H2O (2 mL) was heated under microwave (CEM Discover) conditions at 150° C. for 30 minutes. The mixture was quenched with 1 MHCl (0.4 mL) and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated. The cruconcentrate was purified by reverse phaseHPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (500 MHz, DMSO-d6) δ 12.95 (brs, 1H), 11.44 (s, 1H), 8.34 (d, 1H), 7.88 (d, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.31 (m, 5H), 7.18 (m, 3H), 6.83 (d, 1H), 6.00 (m, 2H), 4.08 (t, 2H), 2.21 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][CH2:28][C:29]3[CH:44]=[CH:43][C:32]([C:33]([O:35]CC4C=CC=CC=4)=[O:34])=[CH:31][CH:30]=3)=[O:26])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:45]2[C@H:49]([OH:50])[C@H:48]([OH:51])[C@@H:47]([C:52]([NH:54][CH2:55][CH3:56])=[O:53])[O:46]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:57]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:21][CH2:22][CH2:23][NH:24][C:25]([NH:27][CH2:28][C:29]3[CH:44]=[CH:43][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)=[O:26])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[C@H:45]2[C@H:49]([OH:50])[C@H:48]([OH:51])[C@@H:47]([C:52]([NH:54][CH2:55][CH3:56])=[O:53])[O:46]2)[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCc4ccc(C(=O)OCc5ccccc5)cc4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CCO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCc4ccc(C(=O)O)cc4)nc32)[C@H](O)[C@@H]1O
Yield: 19.2 %

Procedure:
A solution of benzyl 4-[({[(2-{[(6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purin-2-yl)carbonyl]amino}ethyl)amino]carbonyl}amino)methyl]benzoate (Preparation 55) (150 mg, 0.18 mmol) in ethanol (10 ml) was hydrogenated at room temperature over 10% w/w palladium-on-carbon (30 mg) for 28 hours at 414 KPa. The catalyst was removed by filtration through Arbocel (trade mark) and solvent evaporated under reduced pressure to afford the title compound as a white powder (26 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9]Cl)=[C:4]([CH3:11])[N:3]=1.[CH:12]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[C:15]([CH3:16])[C:13]=1[OH:14].CC([O-])(C)C.[K+]>CC(N(C)C)=O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH2:9][O:14][C:13]2[CH:12]=[C:19]([CH:20]([CH3:21])[CH3:22])[CH:18]=[CH:17][C:15]=2[CH3:16])=[C:4]([CH3:11])[N:3]=1
Reactant: Cc1nc(Cl)nc(Cl)c1CCl
Reactant: Cc1ccc(C(C)C)cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(C)C)cc1OCc1c(C)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-dichloro-5-chloromethyl-6-methyl-pyrimidine (17.4 g, 82.7 mmol) and carvacrol (6.21 g, 41.4 mmol) in DMA (166 mL) at 0° C. under nitrogen with magnetic stirring is added KOtBu (42 mL of 1 M in THF, 42 mmol) in dropwise fashion over 20 min. The resulting redish-orange colored solution is allowed to slowly warm to ambient temperature (˜2 h) and stir for 18 h. The reaction mixture is re-cooled to 0° C. and another portion of carvacrol is added (6.21, 41.4 mmol) followed by dropwise addition of KOtBu (42 mL of 1 M in THF, 42 mmol). The reaction mixture is allowed to slowly warm to ambient temperature (˜2 h) and stir for 18 h. The reaction mixture is partitioned between EtOAc (200 mL) and water (60 mL), the organic layer is separated, washed with water (60 mL×3), brine (60 mL), dried over sodium sulfate, filtered and evaporated at reduced pressure to obtain an orange oil. The crude product is dissolved in hexanes (300 mL), quickly extracted with Claisen's alkali (50 mL×2), dried over sodium sulfate, filtered and evaporated to obtain an orange oil. Purification by chromatography on silica gel (10 EtOAc/Hexanes) provides the title compound as a colorless oil that solidifies on standing. LC/MS (Method 3), M+H=325.2, Rt=3.03 min.; 1H NMR (CDCl3) δ=7.09 (d, 1H), 6.82 (d, 1H), 6.81 (s, 1H), 5.17 (s, 2H), 2.90 (m, 1H), 2.68 (s, 3H), 2.14, (s, 3H), 1.26 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.[Cl:28]N1C(=O)CCC1=O>O1CCCC1.CCOCC>[Cl:28][C:15]1[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)=[C:11]2[CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Fc1ccc(-c2nn3ccccc3c2-c2ccncc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: Fc1ccc(-c2nn3c(Cl)cccc3c2-c2ccncc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (100 mg, 0.346 mmol) in 4 ml of tetrahydrofuran at −78° C. under N2 was added 2.5 M n-butyllithium in hexanes (22 μl, 2 eq). The mixture was stirred at −78° C. for 30 min and N-chlorosuccinimide (2.2 eqv) was then added. The mixture was allowed to warm to room temperature after 30 min and was stirred at room temperature for 1 hr. The mixture was diluted with ether and washed with 1N hydrochloric acid solution. The aqueous layer was basified with 1N sodium hydroxide solution and extracted thoroughly with ether. The combined organic layers were dried on anhydrous magnesium sulfate, filtered and evaporated. Purification by chromatography yielded 7-chloro-2-(4-fluorophenyl)-3-(4-pyridinyl)pyrazolo[1,5-α]pyridine (71%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[C:16]([OH:18])=[O:17].OS(O)(=O)=O.[CH3:24]O>>[OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][C:7]=1[C:16]([O:18][CH3:24])=[O:17]
Reactant: NS(=O)(=O)c1ccc(SCCCO)c(C(=O)O)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(S(N)(=O)=O)ccc1SCCCO

Procedure:
4-(3-hydroxypropylthio)-3-carboxybenzene-sulfonamide (15 g, 0.0515 mol) and concentrated H2SO4 (4 ml) were dissolved in methanol (150 ml) and refluxed on a steam bath for about 5 hours. The solvent was removed and the residue was treated with water. The mixture was extracted with ethylacetate, which was washed with water, saturated sodium bicarbonate, water and brine. After drying, removal of the solvent left a tannish solid. Recrystallization from 1,2-dichloroethane gave 13.5 g of a white solid. M.p.=123°-125°.