Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>>[NH:10]([C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:11]
Reactant: Cc1cccnc1Br
Reactant: NN
Solvent: O
Product: Cc1cccnc1NN
Temperature: 100 °C
Reaction time: 4 h
Yield: 60.1 %

Procedure:
The title compound was prepared according to the procedure described in U.S. Pat. No. 4,260,767 (1981). A mixture of 2-bromo-3-methylpyridine (29.0 g, 169 mmol) and hydrazine monohydrate (60 mL, 1.24 mol) was heated and stirred at 100° C. for 4 hours. The mixture was ice cooled, and the resulting crude crystals were filtered. The crystals were washed with cold water and air dried, and recrystallized from chloroform/hexane to give the title compound (12.5 g, 60% yield).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:28][C:29]([OH:46])([CH3:45])[CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:27]=[CH:26][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH2:19][C:20]6[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=6)[N:16]=[CH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:33]=[N:32]1
Reactant: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccccn3)nc1-2
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3c(c2)OCCc2sc(-c4ncnn4Cc4ccccn4)nc2-3)cn1

Procedure:
Following the procedure for 114, 8-Bromo-2-(2-pyridin-2-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 2-Methyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propan-2-ol to give 417. MS(ESI+) 500.1. 1H NMR (400 MHz, CDCl3) δ 8.56-8.52 (d, J=4.2, 1H), 8.19 (s, 1H), 8.14 (s, 1H), 8.03 (d, J=8.3, 1H), 7.92 (s, 1H), 7.78 (td, J=7.7, 1.8, 1H), 7.32-7.26 (m, 2H), 7.24 (d, J=1.7, 1H), 7.16 (d, J=7.9, 1H), 6.17 (s, 2H), 4.71 (s, 1H), 4.34 (t, J=5.0, 2H), 4.03 (s, 2H), 3.41 (t, J=5.0, 2H), 1.09 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](Cl)=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH2:24][CH3:25])[CH3:15]>ClCCl>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]([C:21]1[CH:20]=[CH:19][C:18]([O:23][CH2:24][CH3:25])=[C:17]([O:16][CH2:14][CH3:15])[CH:22]=1)=[O:7]
Reactant: CCOc1ccccc1OCC
Reactant: COC(=O)CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)CCC(=O)OC)cc1OCC
Reaction time: 14 h

Procedure:
1.1 A solution of 70 ml 3-chlorocarbonyl-propionic acid methyl ester in 100 ml dichloromethane is added to a suspension of 80.0 g of AlCl3 in 300 ml dichloromethane at 20-25°. At 0° a solution of 85.0 g 1,2-diethoxybenzene in 100 ml dichloromethane is added. The solution is tirred for 14 hours at room temperature. Work-up is as usual, yielding 122.2 g of 4-(3,4-diethoxy-phenyl)-4-oxo-butyric acid methyl ester (“AA”), m.p. 84-85°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:14][CH2:13][C:12]1=[O:15]>>[C:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:14][CH2:13][C:12]2=[O:15])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: O=C1CCN1
Reactant: CC(=O)c1cccc(Br)c1
Product: CC(=O)c1cccc(N2CCC2=O)c1
Yield: 97 %

Procedure:
The title compound was prepared in 97% yield according to the general procedure for the preparation of the amides, ureas and carbamates (Method A) starting from 1-(3-bromophenyl)ethanone and 2-azetidinone.
Reaction SMILES: [C:1]1([S:7]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)(=[NH:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19]Cl>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][N:9]=[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CN(C)CCCCl
Reactant: N=S(=O)(c1ccccc1)c1cccs1
Product: CN(C)CCCN=S(=O)(c1ccccc1)c1cccs1
Yield: 38 %

Procedure:
In a manner analogous to that described in Example 1, Stage 3, by the reaction of phenyl-(2-thienyl)-sulphoximide with 3-dimethylaminopropyl chloride, there is obtained, in a yield of 38% of theory, N-(3-dimethylaminopropyl)-S-phenyl-S-(2-thienyl)-sulphoximide, the fumarate of which, after recrystallisation from ethyl acetate/isopropanol, melts at 125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][CH:3]=1.[O-:10][C:11]#[N:12].[K+]>C(O)(=O)C.O>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:11]([NH2:12])=[O:10])[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: Cc1ccc(N)cc1O
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc(NC(N)=O)cc1O
Temperature: 0 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
5-Amino-o-cresol (1 g, 8.12 mmol) was dissolved in glacial acetic acid (4.1 mL) and H2O (8.41E) ata 35° C. The potassium cyanate solution was added slowly with stirring until a with precipitate of the product appears. The rest is added quickly with vigorous agitation. After 24 h, the reaction mixture was diluted with H2O, cooled to 0° C. and filtered with suction, washed with H2O and dried under high vacuum to afford the product (1.3 g, 99% yield).
Reaction SMILES: CC(N(C)C)=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:23][C:24]2[C:29]3[C:30]4[CH2:38][CH2:37][C:36]5[C:32](=[CH:33][N:34]([CH2:39][CH2:40][OH:41])[N:35]=5)[C:31]=4[S:42][C:28]=3[N:27]=[CH:26][N:25]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1.Cl[S:44]([NH2:47])(=[O:46])=[O:45]>[Cl-].[Na+].O>[S:44](=[O:46])(=[O:45])([O:41][CH2:40][CH2:39][N:34]1[CH:33]=[C:32]2[C:36]([CH2:37][CH2:38][C:30]3[C:29]4[C:24]([NH:23][C:10]5[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]6[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=6)=[C:8]([Cl:7])[CH:9]=5)=[N:25][CH:26]=[N:27][C:28]=4[S:42][C:31]=32)=[N:35]1)[NH2:47]
Reactant: NS(=O)(=O)Cl
Reactant: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NS(=O)(=O)OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 26.3 %

Procedure:
To 5 mL DMA cooled to 5° C. was added 2-[6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl]ethanol (100 mg, 0.19 mmol) followed by chlorosulfonyl amine (221 mg, 1.9 mmol). The mixture was stirred with warming to rt over a 2 h period, after which time stirring was halted. The entire mixture was poured onto cold brine (10 mL), upon which precipitation of a solid occurs. The mixture was filtered, and the filtrate extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude residue was purified by reverse phase HPLC. The product fractions were combined and diluted with CH2Cl2 (50 mL), and neutralized with NaHCO3 (50 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to afford the final pure product (30 mg, 26%) as a white solid. 1H-NMR (DMSO-d6) δ 8.40 (s, 1H), 8.33 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.59 (s, 2H), 7.51 (dd, 1H), 7.40 (dd, 1H), 6.91-7.11 (m, 4H), 5.21 (s, 2H), 4.38 (br s, 4H), 3.32 (t, 2H), 2.90 (t, 2H); LCMS RT=3.45 min; [M+H]+=601.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([C@H:15]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:16]3[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([C@@H:15]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:16]3[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:23][CH3:24])[CH2:25][CH3:26])=[O:21])=[CH:18][CH:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(Nc3cccc(Cl)c3)c2)N2CCNCC2)cc1
Solvent: CO
Product: CCN(CC)C(=O)c1ccc([C@@H](c2cccc(Nc3cccc(Cl)c3)c2)N2CCNCC2)cc1

Procedure:
To a solution of INTERMEDIATE 5a (103 mg) in toluene (2 mL) was added 3-chloro-bromobenzene (34 μL; 1.3 eq), Pd2(dba)3 (8.2 g; 0.04 eq), Sodium tert-butoxide (29 g; 1.4 eq) and BINAP (11 g; 0.08 eq). The solution was heated in the microwave in a sealed tube for 5 min at 110° C. The resulting mixture filtered through celite and concentrated. The crude was purified by a normal phase MPLC with a disposable silica gel column (40 g); eluting 40% to 60% ethyl acetate in hexane. Pure fraction collected and concentrated to afford yellow foam. The resulting product was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) was added and the solution stirred for 18 hours until complete removal of the boc group. The reaction was concentrated and diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate. The aqueous was extracted with two portions of dichloromethane and the combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to about 2 mL of solvent. In the solution was added 560 μL of 1M HCl in ether and the solvent was removed and the product was isolated as the hydrochloride salt to give COMPOUND 30 (77 mg, 73% yield) as beige solid. Purity (HPLC): >99%; Optical purity (Chiral HPLC): >99%; 1H NMR (400 MHz, CD3OD) 1.07 (t, J=6.40 Hz, 3H), 1.20 (t, J=6.64 Hz, 3H), 3.05-3.27 (m, 6H), 3.43-3.57 (m, 6H), 6.80 (dd, J=8.01, 1.27 Hz, 1H), 6.92 (dd, J=8.15, 1.51 Hz, 1H), 6.99 (t, J=2.00 Hz, 1H), 7.00-7.04 (m, 1H), 7.13-7.17 (m, 2H), 7.27 (t, J=7.76 Hz, 1H), 7.39 (br s, 1H), 7.41 (d, J=7.81 Hz, 2H), 7.75 (d, J=6.74 Hz, 2H). [a]D20=+20.77 deg [c 0.467, MeOH].
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(C(F)(F)F)=O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[B:20]([OH:22])[OH:21]>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([N+:1]([O-:4])=[O:2])=[CH:15][C:14]=1[B:20]([OH:21])[OH:22]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(B(O)O)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c([N+](=O)[O-])cc1B(O)O
Temperature: -35 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To fuming nitric acid (1 ml) cooled to −40° C. was added TFA (1 ml). The resulting mixture was allowed to warm slightly to −35° C. and 2,4-dimethyl phenyl boronic acid (150 mg, 1 mmol) was added in one portion. After 1 h, ice was added and the heterogenous mixture was filtered. The resulting solid was suspended in Et2O and extracted with 3N NaOH (aq) (1 ml) then water (2 ml). The aqueous phase was acidified with 3N HCl (aq) (1 ml) and back extracted with EtOAc (3×5 ml). The pooled organics were washed with brine, dried with Na2SO4 decanted and concentrated to give 2,4-dimethyl-5-nitro-phenyl boronic acid (93 mg, 47%). LCMS (ESI+) [M+H]/z Calc'd 196, found 196.
Reaction SMILES: [Mg].[CH3:2][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([CH3:16])[C:10](=[O:15])[CH2:11][C:12]([O-:14])=O)[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:25]O>>[CH3:2][C:3]1[O:8][CH2:7][N:6]([C:9]([CH3:17])([CH3:16])[C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:25])[C:5](=[O:18])[C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CO
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)CC(=O)[O-])CO1
Agent: [Mg]
Product: CC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A suspension of magnesium turnings (100 mg) in methanol was stirred whilst a solution of t-butyl [4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (1.40 g) in methanol was added. The mixture was heated at 60° C. for 1 hour, cooled and evaporated. Toluene was added and the mixture re-evaporated. The residue was redissolved in toluene and a solution of acetyl chloride (300 mg) added. The mixture was stirred at 20° C. for 1 day, then hydrochloric acid (2M) added and the stirring continued for another 1 hour. The organic phase was washed with hydrochloric acid (2M) then with water and dried (magnesium sulphate) 4-Toluene-sulphonic acid (50 mg) was added and the mixture stirred at 80° C. for 1 hour, cooled and washed in turn with saturated sodium bicarbonate solution and water, dried (magnesium sulphate) and evaporated to give 5-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-1,3-oxazin-3-yl)-5-methyl-2,4-hexanedione (Compound 193, 0.15 g) as a brown gum, NMR 1.56(s,6H), 1.91(s,3H), 2.15(s,3H), 3.66 and 3.70(s,1H), 5.25(t,2H), 7.20-7.44(m,5H).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([O:19]C(C)C)=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:3][CH:2]=1.CO.[OH-].[Na+]>O>[C:1]1([CH3:23])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[N:13]3[CH2:14][CH2:15][CH:16]([C:17]([OH:19])=[O:18])[C:12]3=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)OC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)c2ccc3n2CCC3C(=O)O)cc1

Procedure:
A solution of 250 mg. of isopropyl 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate in 8 ml. of methanol is treated under an atmosphere of nitrogen, with a solution of 200 mg. of sodium hydroxide in 1 ml. of water, maintaining the reaction mixture at room temperature for 1.5 hours. The methanol is then removed under reduced pressure and the basic solution which remains is diluted with 5 ml. of water and extracted with ether to remove any unsaponifiable product. The aqueous solution is acidified with 10% hydrochloric acid and extracted three times with ethyl acetate. The combined extracts are dried and evaporated to dryness under reduced pressure, and the residue crystallized from ethyl acetate-hexane, to give 5-p-toluoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid, identical to the product obtained in Example 9.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8][C:7]1([CH3:15])[CH3:14].C(O[Cl:21])(C)(C)C>CO>[Cl:21][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[C:7]1([CH3:15])[CH3:14]
Reactant: CC1(C)NC(C)(C)N(CCCCO)C1=O
Reactant: CC(C)(C)OCl
Solvent: CO
Product: CC1(C)C(=O)N(CCCCO)C(C)(C)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To a 0° C. solution of 3-(4-hydroxybutyl)-2,2,5,5-tetramethylimidazolidin-4-one, (622 mg, 2.9 mmol) in methanol (80 ml) was added tert-butylhypochlorite (473 mg, 4.4 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 15% methanol in dichloromethane) to give 213 mg (30%) of the title compound. 1H NMR (400 MHz, D2O) δ 3.74-3.66 (m, 2H), 3.34-3.30 (m, 2H), 2.08 (s, 1H), 1.78-1.71 (m, 2H), 1.65-1.57 (m, 2H), 1.47 (s, 6H), 1.36 (s, 6H). 13C NMR (100 MHz, D2O) δ 173.0, 82.3, 65.5, 62.5, 40.5, 29.8, 26.1, 25.5, 23.8. LRMS (ESI/APCI) m/z 249 [M+H]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][CH2:12][O:13]C(C)=O.[C:17]([C:20]1[C:21]([NH:28][C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)=[N:22][C:23]([S:26][CH3:27])=[N:24][CH:25]=1)(=O)[CH3:18]>C1COCC1>[CH3:18][C:17]1[C:20]2[CH:25]=[N:24][C:23]([S:26][CH3:27])=[N:22][C:21]=2[N:28]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=[CH:33][CH:34]=2)[C:12](=[O:13])[CH:11]=1
Reactant: CSc1ncc(C(C)=O)c(Nc2cccc(NC(=O)OC(C)(C)C)c2)n1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ncc2c(C)cc(=O)n(-c3cccc(NC(=O)OC(C)(C)C)c3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
LiHMDS (1.0 M in THF, 27.3 mL, 27.3 mmol) was added to THF (100 mL) at −78° C. and treated with EtOAc (2.50 mL, 25.6 mmol) and stirred 15 min. tert-Butyl (3-((5-acetyl-2-(methylthio)pyrimidin-4-yl)amino)phenyl)carbamate (53) (3.19 g, 8.52 mmol) was added in one portion at −78° C. and the solution warmed to RT and stirred for 3 h. The reaction mixture was quenched with a saturated solution of NH4Cl and extracted with EtOAc (150 mL), washed with brine and dried over MgSO4, filtered and concentrated. Purification of the crude residue on silica gel column (10-90% EtOAc in hexanes) afforded the title compound (54) (2.49 g, 6.25 mmol, 73% yield) as a light yellow amorphous solid. m/z (ESI, +ve ion) 398.9 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, s), 7.46 (1H, br. s.), 7.42 (1H, t, J=8.0 Hz), 7.31 (1H, dd, J=8.2, 1.4 Hz), 6.87-6.94 (1H, m), 6.50-6.59 (2H, m), 2.50 (3H, d, J=1.0 Hz), 2.17 (3H, s), 1.50 (9H, s).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([C:20]#[CH:21])[CH:17]=[C:16]([Cl:22])[CH:15]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[CH2:27]([O:26][C:24](=[O:25])[C:21]#[C:20][C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[C:16]([Cl:22])[CH:17]=1)[CH3:28]
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C#Cc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
To a solution of diisopropylamine (0.23 mL) in THF (0.6 mL) at −78° C. was added a solution of n-butyllithium (0.46 mL, 2.0 M in hexane). The mixture was stirred at −78° C. for 20 minutes, 0° C for 15 min., and cooled to −78° C. To this mixture was added a solution of 1,3-dichloro-5-ethynyl-benzene (136 mg, 0.80 mmol) in THF (1.0 mL) over 2 minutes. After stirring at −78° C. for 1 h, a solution of ethyl chloroformate (0.09 mL) in THF (0.2 mL) was added, and stirred for 1 h at −78° C. The reaction was quenched with saturated ammonium chloride, warmed up to ambient temperature, and extracted with ethyl acetate. The extract was dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with hexane to give the title compound (0.16 g, 87% yield) as a yellow oil. 1H NMR (CDCl3) δ 7.47-7.44 (m, 3H), 4.31 (q, 2H, J=7.2 Hz), 1.36 (t, 3H, J=7.2 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.Cl.Cl.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[ClH:14].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[CH2:9][S:8][CH2:7]3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=C1CSCN1CCCCBr
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CSCN1CCCCN1CCN(c2ccc(Cl)cc2)CC1

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (3.0 g) and 1-(4-chlorophenyl)piperazine dihydrochloride (3.4 g) in 100 ml of anhydrous CH3CN were added K2CO3 (8.7 g) and KI (200 mg). The mixture was heated to 80° with stirring under N2.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[NH2:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:50])=[C:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=2)[CH:41]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:31]=[CH:30][CH:29]=[C:25]([C:26]([NH:34][CH2:35][C:36]4[CH:41]=[C:40]([C:42]5[CH:47]=[CH:46][CH:45]=[C:44]([CH2:48][OH:49])[CH:43]=5)[C:39]([F:50])=[CH:38][CH:37]=4)=[O:27])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: NCc1ccc(F)c(-c2cccc(CO)c2)c1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CO)c3)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (446 mg, 1 mmol) in DMF (70 mL) was added [5′-(aminomethyl)-2′-fluoro-3-biphenylyl]methanol (230 mg, 1 mmol), PyBOP (570 mg, 1.1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) and the mixture was stirred at ambient temperature for 16 h. Additional PyBOP (518 mg, 1 mmol) and diisopropylethylamine (0.69 mL, 4 mmol) were added and the mixture stirred for an additional 2 h. The mixture was then concentrated to dryness and the residue was treated with water (400 mL) and extracted with dichloromethane (2×200 mL). The combined organics were dried (hydrophobic frit) and concentrated in vacuo and the resulting yellow oil was subjected to purification by flash chromatography (100 g silica cartridge, gradient elution from 0-100% ethyl acetate/cyclohexane) to afford 650 mg of the title compound. LC-MS m/z 665 (M+H)+, 0.98 min (ret time).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([NH:5][NH2:6])=O.[I:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:13](=[NH:17])OCC>CO>[I:9][C:10]1[CH:11]=[C:12]([C:13]2[NH:17][C:3]([C:2]([F:8])([F:7])[F:1])=[N:5][N:6]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: CCOC(=N)c1ccc(C)c(I)c1
Reactant: NNC(=O)C(F)(F)F
Solvent: CO
Product: Cc1ccc(-c2nnc(C(F)(F)F)[nH]2)cc1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
2,2,2-Trifluoroacetohydrazide (0.14 g, 1.0 mmol) was added to a stirred solution of ethyl 3-iodo-4-methylbenzimidate (preparation 51b, 0.30 g, 1.0 mmol) in methanol (3 mL) and the mixture was stirred and heated to 70° C. After 2 hours, the mixture was cooled and concentrated in vacuo. The residue was purified by flash chromatography (5:1 hexanes/ethyl acetate) to give the title compound (0.10 g, 27%) as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([OH:11])[N:5]2[N:4]=1.[N-:14]=[N+:15]=[N-:16].[Na+]>CN(C)C=O>[N:14]([CH2:2][C:3]1[N:13]=[C:6]2[N:7]=[C:8]([CH3:12])[CH:9]=[C:10]([OH:11])[N:5]2[N:4]=1)=[N+:15]=[N-:16]
Reactant: Cc1cc(O)n2nc(CBr)nc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(O)n2nc(CN=[N+]=[N-])nc2n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.8 %

Procedure:
2-Bromomethyl-5-methyl[1.2.4]triazolo[1,5-a]pyrimidin-7-ol (3.6 g) are dissolved in 50 ml of dimethylformamide, treated with 0.99 g of sodium azide and stirred at room temperature for 2.5 hours. The dimethylformamide is evaporated in a high vacuum at 40° C. and the residue is treated with 35 ml of water. The thus-obtained suspension is stirred in an ice bath for 45 minutes. A white precipitate is filtered off under suction, washed with a small amount of water and dried in a high vacuum. There are obtained 2.0 g of 2-azidomethyl-5-methyl[1.2.4]-triazolo[1,5-a]pyrimidin-7-ol as white crystals of melting point 193°-194° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:17]2[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([CH:26]=[O:27])[C:18]=2[CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(C)=O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([C:17]2[C:18]([CH3:28])=[C:19]([CH2:26][OH:27])[C:20]([CH3:25])=[C:21]([CH3:24])[C:22]=2[OH:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1c(C)c(C=O)c(C)c([C@H](CCCCCC(=O)O)c2ccc(F)cc2)c1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c(CO)c(C)c([C@H](CCCCCC(=O)O)c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of (R)-7-(4-fluorophenyl)-7-(3-formyl-6-hydroxy-2,4,5-trimethylphenyl)heptanoic acid (0.43 g, 1.1 mmol) in tetrahydrofuran (7 ml) was added, under ice-cooling, sodium borohydride (21.0 mg). The mixture was stirred for two hours at room temperature, to which was added acetone, then the solvent was distilled off under reduced pressure. The residue was neutralized with 1N HCl, which was subjected to extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous saline solution, followed by drying over magnesium sulfate. The solvent was distilled off under reduced pressure to leave 0.38 g of (R)-7-(4-fluorophenyl)-7-(2-hydroxy-5-hydroxymethyl-3,4,6-trimethylphenyl)heptanoic acid, whose spectral data are shown in [Table 4].