Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([O:20]C(C)(C)C)=[O:19])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([OH:20])=[O:19])[C:13]1=[O:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C(=O)O)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
tert-Butyl(2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (0.5 g) was dissolved in DCM (7 ml), and trifluoroacetic acid (4.7 ml) was added. The mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure to give the title compound (0.423 g) as a colourless oil, which after azeotroping with toluene, crystallised.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:23]=[CH:22]C(C#N)=[CH:18][CH:17]=1)[N:11]=2.[C:24]([OH:27])(=[O:26])[CH3:25].OS(O)(=O)=O>O>[CH3:1][C:2]1[O:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[C:10]2[C:14]=1[C:13](=[O:15])[N:12]([C:16]1[CH:17]=[CH:18][C:25]([C:24]([OH:27])=[O:26])=[CH:22][CH:23]=1)[N:11]=2
Reactant: Cc1oc2ccccc2c2nn(-c3ccc(C#N)cc3)c(=O)c1-2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1oc2ccccc2c2nn(-c3ccc(C(=O)O)cc3)c(=O)c1-2
Temperature: 100 °C

Procedure:
A mixture of 4-(4-methyl-3-oxo-3H-chromeno[4,3-c]pyrazol-2-yl)-benzonitrile (0.030 g, 0.10 mmol), acetic acid (0.4 ml), H2SO4 (0.4 ml) and water (0.4 ml) was heated at 100° C. in an oil bath for 19 h. After cooling water was added and the precipitation collected, washed with water and dried to yield 4-(4-methyl-3-oxo-3H-chromeno-[4,3-c]pyrazol-2-yl)-benzoic acid (0.029 g): 1H NMR (400 MHz, DMSO-d6) δ 8.21 (2H, d), 8.13 (1H, d), 8.01 (2H, d), 7.67-7.75 (2H, m), 7.54-7.58 (1H, m), 2.78 (3H, s); ESI MS m/z 321 (M+H+).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[CH3:8][C:9]1([CH3:22])[C:13]([CH3:15])([CH3:14])[O:12][B:11]([C:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH:21]=2)[O:10]1.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:15][C:13]1([CH3:14])[C:9]([CH3:22])([CH3:8])[O:10][B:11]([C:16]2[CH2:17][CH2:18][N:19]([C:6]([NH2:5])=[O:7])[CH2:20][CH:21]=2)[O:12]1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC1(C)OB(C2=CCNCC2)OC1(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)OB(C2=CCN(C(N)=O)CC2)OC1(C)C
Reaction time: 3 h

Procedure:
Trimethylsilyl isocyanate (0.2205 mL, 1.629 mmol) was added to a room temperature solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (200.0 mg, 0.8145 mmol) and DIPEA (0.5675 mL, 3.258 mmol) in DCM (10 mL). The mixture was stirred for 3 hours, after which, it was partioned between DCM and sat. NaHCO3. The organic layer was concentrated in vacuo to afford the title compound as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:29])=[C:7]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)=[O:4].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([CH2:30][CH3:31])[C:7]2[CH:8]=[C:9]([C:11]([F:13])([F:14])[F:12])[CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:6]=2[CH3:29])[CH2:21][CH2:20]1)=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCN(c1cc(C(F)(F)F)cc(C(=O)OC)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 23 °C
Reaction time: 24 h
Yield: 39.9 %

Procedure:
To a stirred solution of tert-butyl 4-{[3-(methoxycarbonyl)-2-methyl-5-(trifluoromethyl)phenyl]amino}piperidine-1-carboxylate (10.6 g, 25.4 mmol) in CH2Cl2 (200 mL) and AcOH (10 mL) was added acetaldehyde (2.80 g, 63.5 mmol) and sodium triacetoxyborohydride (13.4 g, 63.5 mmol). The reaction mixture was stirred at 23° C. for 24 hours. Then saturated NaHCO3 was added and the mixture was separated. The aqueous layer was extracted with CH2Cl2 (3×50 mL) and the combined organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (SiO2 Heptane/EtOAc=5/1) to give the titled compound as oil (4.50 g, 40% yield). 1H-NMR (400 MHz, CDCl3) δppm; 7.82 (br. s., 1H), 7.45 (d, J=1.6 Hz, 1H), 3.96-4.18 (m, 2H), 3.92 (s, 3H), 3.08 (q, J=7.0 Hz, 2H), 2.89 (tt, J=11.0, 3.7 Hz, 1H), 2.69 (m, 2H), 2.55 (s, 3H), 1.73 (m, 2H), 1.49-1.56 (m, 2H), 1.45 (s, 9H), 0.86 (t, J=7.0 Hz, 3H); MS (ES) [M+Na] 467.0.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([OH:23])=[C:18]([CH3:24])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].CC(=O)OCC>[CH3:22][C:20]1[CH:21]=[C:16]([C:13]2[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[O:15][N:14]=2)[CH:17]=[C:18]([CH3:24])[C:19]=1[O:23][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: ClCC1CO1
Reactant: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2noc(-c3ccc(OC(C)C)cc3)n2)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A mixture of 4-[5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (370 mg, 1.14 mmol) and epichlorohydrine (317 mg, 3.42 mmol) in isopropanol (5 mL) and 3 N aq. NaOH (1.5 mL) is stirred at rt for 16 h. The mixture is diluted with EA, washed with water, dried over MgSO4, filtered and concentrated. The crude product is purified by chromatography on prep. TLC plates with heptane:EA 3:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(4-isopropoxy-phenyl)-[1,2,4]oxadiazole (256 mg) as white solid; LC-MS: tR=1.14 min, [M+1]+=381.18.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:23])[CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:21])[CH3:20])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].N1C=CC=CC=1.[C:30](Cl)(=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].C(=O)([O-])O.[Na+]>ClCCl>[Br:1][CH2:2][CH:3]([O:23][C:30](=[O:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:4][O:5][C:6](=[O:22])[C@H:7]([CH:19]([CH3:20])[CH3:21])[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(O)CBr
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCC(=O)OC(CBr)COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 3-bromo-2-hydroxy-1-(N-CBZ-L-valyloxy)-propane (7.9 g, 20 mmol) and pyridin (3.2 g, 40 mmol) in 250 ml dichloromethane was added dropwise a solution of stearoyl chloride (9.1 g, 30 mmol) in 50 ml dichloromethane between 10° C. and 15° C. The solution was stirred overnight at room temperature. 150 ml of 5% sodium hydrogen carbonate solution was added and the mixture stirred for 30 minutes. The organic phase was separated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromtography. Yield: 10.5 g
Reaction SMILES: CS(C)=O.[H-].[Na+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]#[N:16])=[CH:10][CH:9]=1.Br[CH2:18][CH2:19][CH2:20]Br>C(OCC)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:15]#[N:16])[CH2:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Yield: 68.2 %

Procedure:
Into a round-bottom flask under argon fitted with an addition funnel and thermometer was added anhydrous dimethylsulfoxide and sodium hydride (1.17 g, 48.8 mmol, 95%). Then a solution of (4-chlorophenyl)acetonitrile (A) (2.70 mL, 22.2 mmol) and 1,3-dibromopropane (2.48 mL, 24.4 mmol) in diethyl ether (15 mL) was added slowly, while maintaining the reaction temperature at 20-30° C. The reaction mixture was maintained at room temperature for overnight. The reaction mixture was carefully quenched with water (50 mL) and then extracted with hexane (3×100 mL). The organic extracts were combined, washed with water (3×75 mL), brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2.9 g of 1-(4-chlorophenyl)-cyclobutanecarbonitrile, B, as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 2.03-2.09 (m, 1H); 2.36-2.62 (m, 3H); 2.76-2.84 (m, 2H); 7.34 (s, 4H); 13C NMR (CDCl3, 75 MHz): δ 17.0, 34.6 (2C), 39.7,123.9, 127.1, 129.1, 133.7, 138.3.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][O:40][Si](C(C)(C)C)(C)C)[C:34]([CH3:48])=[CH:33][C:32]=1[S:49]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CO.Cl>[C:27]([C:31]1[CH:36]=[C:35]([O:37][CH2:38][CH2:39][OH:40])[C:34]([CH3:48])=[CH:33][C:32]=1[S:49][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCCO[Si](C)(C)C(C)(C)C)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1OCCO

Procedure:
The title compound was synthesized using General Method 9 using 0.07 g (2 mmol) of 4-hydroxy-6,6-bis-[2-(4-hydroxy-phenyl)-ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 1.00 g (2 mmol) of toluene-4-thiosulfonic acid S-{2-tert-butyl-4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-methyl-phenyl} ester (prepared in Example PPP), 1.06 g (8 mmol) K2CO3, and DMF (5 mL). The solid which was obtained was then dissolved in 20 mL MeOH and 2 mL of 1N HCl. After 15 minutes the reaction was concentrated and the residue partitioned between EtOAc and H2O; the organic layer was separated, dried (Na2SO4) and concentrated. Trituration with Et2O yielded the title compound, m.p. 106°-107° C. 1H NMR (DMSO-d6) δ 1.49 (s, 9 H), 1.75 (s, 3 H), 2.0 (t, 4 H), 2.5 (t, 4 H), 3.4 (dd, 2 H), 3.7 (bs, 2 H), 3.95 (t, 2 H), 4.8 (br s, 1 H), 6.66 (d, 4 H), 6.7 (s, 1 H), 6.8 (s, 1 H), 6.98 (d, 4 H), 9.17 (s, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:3]=1[C:4]#[N:5].[S:13](Cl)(=[O:16])(=[O:15])[NH2:14]>>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:9][C:2]=1[NH:1][S:13]([NH2:14])(=[O:16])=[O:15])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: CC(C)c1ccc(N)c(C#N)c1
Product: CC(C)c1ccc(NS(N)(=O)=O)c(C#N)c1

Procedure:
Prepared as in Example 77a from 2-Amino-5-isopropylbenzonitrile (Example 87b) and sulfamoyl chloride.
Reaction SMILES: [C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[C:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCC(=O)Oc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCCC(=O)Oc1ccc(C(=O)Cl)cc1
Yield: 81.6 %

Procedure:
A mixture of 10 g of the resultant 4-hexanoyloxybenzoic acid, 8 g thionyl chloride and 100 ml toluene was stirred and externally heated to be refluxed for three hours. After distilling off the toluene from the mixture, the residue was distilled under reduced pressure to give 8.8 g 4-hexanoyloxybenzoic acid chloride in 82% yield based upon the amount of the 4-hexanoyloxybenzoic acid.
Reaction SMILES: N(OC(C)(C)C)=O.[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N+:16]([O-:22])=[C:17](N)[N:18]=[N+:19]([O-:20])[C:14]=2[CH:13]=1)[CH:9]=[CH2:10]>CN(C=O)C>[CH2:8]([O:11][C:12]1[CH:24]=[CH:23][C:15]2[N+:16]([O-:22])=[CH:17][N:18]=[N+:19]([O-:20])[C:14]=2[CH:13]=1)[CH:9]=[CH2:10]
Reactant: C=CCOc1ccc2c(c1)[n+]([O-])nc(N)[n+]2[O-]
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2c(c1)[n+]([O-])nc[n+]2[O-]
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a stirred solution of t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) in DMF (15 ml) at 60°-65° C. was added 7-allyloxy-3-amino-1,2,4-benzotriazine-1,4-dioxide 23 (205 mg, 0.875 mmol) in small portions over 5 min. After 30 min additional t-butyl nitrite (271 mg, 0.312 ml, 2.63 mmol) was added, and shortly thereafter the deep red solution effervesced and lightened appreciably in color over a period of a few minutes. After an additional 30 min the resultant orange solution was reduced under vacuum to a brown solid which was sequentially flash chromatographed (10% EtOAc/CH2Cl2) and crystallized (CH2Cl2 /petroleum ether) to give 72 mg (38% yield) of the product 24 as light orange crystals, mp 147°-148° C. NMR: δ (400 MHz, d6 -acetone) 4.89 (2H, ddd, H-1', J1',2' =5.5, J1',3'cis =J1',3'trans =1.5 Hz), 5.36 (1H, ddd, H-3', J3',2'cis =10.5, J3',3' =3, J3',1' =1.5 Hz), 5.52 (1H, ddd, H-3', J3',2'trans =17.5, J3',3' =3, J3'1' =1.5 Hz), 6.14 (1H, ddt, H-2', J2',3'cis =10.5, J2',1' =5.5 Hz), 7.70 (1H, d, H-8, J8,6 =2.5 Hz), 7.74 (1H, dd, H-6, J6,5 =9.5 J6,8 =2.5 Hz), 8.33 (1H, d, H-5, J5,6 =9.5 Hz), 8.93 (1H, s, H-3). UV: λ 425, 410, 365, 355, 320, 245, 200. MS m/z/(relative intensity) 220(4), 219(34,M+),103(4), 77(4), 75(4), 63(13), 62(4), 42(3), 41(100), 39(16).
Reaction SMILES: [NH2:1][NH2:2].C([Li])CCC.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O>C1COCC1>[CH3:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[N:1][NH2:2])[NH2:22])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: NN
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C(N)=NN)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a stirring solution of hydrazine (3.32 mL, 3.32 mmol, 1 M in THF) in THF (5 mL) at −78° C. was added butyllithium (1.28 mL, 3.05 mmol, 2.5 M in hexanes). After 30 min, a solution of 4′-methyl-[1,1′-biphenyl]-4-carbonitrile (535 mg, 2.77 mmol) in THF (5 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured onto water (150 mL) and stirred vigorously for 1 h. The precipitate was isolated by filtration using water (2×20 mL) and isohexanes (3×20 mL) to wash the filter cake. The solid was dried under vacuum to yield 560 mg (90%) of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazonamide INT-39 as a fine yellow solid. LCMS-ESI (m/z) calculated for C14H15N3: 225; found 226 [M+H]+, tR=1.15 min (Method 10).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2I)[CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]([C:25]([NH:27][CH:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:29]([F:32])([F:31])[F:30])=[O:26])[S:23][CH:24]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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.O1CCOCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:20]2[CH:21]=[C:22]([C:25]([NH:27][CH:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[C:29]([F:32])([F:31])[F:30])=[O:26])[S:23][CH:24]=2)[CH:7]=1
Reactant: CC1(C)OB(c2csc(C(=O)NC(c3ccccn3)C(F)(F)F)c2)OC1(C)C
Reactant: Brc1cnc2c(I)cnn2c1
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: [Na+]
Solvent: C1COCCO1
Product: O=C(NC(c1ccccn1)C(F)(F)F)c1cc(-c2cnn3cc(Br)cnc23)cs1

Procedure:
6-bromo-3-iodopyrazolo[1,5-a]pyrimidine (1 eq) was mixed with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide (1 eq, step B). Dioxane (10 mL) and 1M Na2CO3 (2 eq) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.05 eq) was added in a flow of nitrogen. The temperature was brought to 90° C. The reaction mixture was stirred at this temperature overnight and concentrated. The residue was poured into a 5-fold excess of water. The mixture was extracted with chloroform. The organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by column chromatography (dichloromethane-methanol, 100:1) to give 4-(6-bromopyrazolo[1,5-a]pyrimidin-3-yl)-N-(2,2,2-trifluoro-1-pyridin-2-ylethyl)thiophene-2-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C:14]([C@@H:16]3[O:25][C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@@H:17]3[OH:26])=[O:15])[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([C@H:14]([OH:15])[C@@H:16]3[O:25][C@H:19]4[O:20][C:21]([CH3:24])([CH3:23])[O:22][C@H:18]4[C@@H:17]3[OH:26])[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:27][CH:28]=1
Reactant: Cc1ccc(C(=O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc([C@H](O)[C@@H]2O[C@H]3OC(C)(C)O[C@H]3[C@@H]2O)cc1Cc1ccc(Cl)cc1
Reaction time: 0.08 h
Yield: 99 %

Procedure:
(3-(4-chlorobenzyl)-4-methyl phenyl)((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanone (4, 26.1 g, 64.9 mmol) and CeCl3.7 H2O (29.0 g, 77.9 mmol) were suspended in 520 mL of MeOH. Sodium borohydride (982 mg, 26.0 mmol, dissolved in 10 mL of 1N aqueous NaOH) was added and the reactants slowly went into solution over about 5 minutes. Another 100 mg (2.6 mmol) of sodium borohydride was added to push the reaction to completion. The reaction was stirred for 10 minutes and quenched with 500 mL of saturated aqueous NH4Cl. Most of the MeOH was removed in vacuo and the residual solvents were diluted with a 1:1 (v:v) solution of saturated aqueous NH4Cl:brine. The aqueous layer was extracted three times with 500 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was used without further purification in the next step (26.2 g, 99% yield, >10:1 d.r.). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.14-7.31 (m, 5 H), 7.04 (d, J=8.3 Hz, 2 H), 6.04 (d, J=3.8 Hz, 1 H), 5.24 (t, J=3.4 Hz, 1H), 4.51 (d, J=3.8 Hz, 1 H), 4.14-4.21 (m, 2 H), 4.04 (d, J=1.5 Hz, 1 H), 3.97 (s, 2 H), 2.77 (d, J=3.0 Hz, 1 H), 2.20-2.27 (m, 3 H), 1.46 (s, 3 H), 1.33 (s, 3 H). MS (ES+) [M+NH4]+=422.
Reaction SMILES: Cl[C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:20].CN1CCCC1=O.C(=O)([O-])O.[Na+]>O>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[C:3]3[NH:10][C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cc(Nc2ncnc3cc(-c4ccco4)[nH]c23)ccc1OCc1ccccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
A mixture of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (80 mg), 3-chloro-4-(pyridin-2-ylmethoxy)aniline (94 mg) and 1-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140° C. for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mL×2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→0:1). The object fraction was concentrated under reduced pressure. Chloroform-diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60° C. to give the title compound (71 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]1(B2OC(C)(C)C(C)(C)O2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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:8]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Reactant: Brc1cccnc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C1=C(c2cccnc2)CCCC1
Yield: 90.9 %

Procedure:
A solution of 3-bromopyridine (0.38 g, 2.40 mmol), 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol) and cesium carbonate (1.72 g, 5.29 mmol) in 1,4-dioxane (8.0 mL) and water (4.0 mL) was stirred at 90° C. for 4 hours. After allowing to cool, the reaction solution was subjected to extraction with ethyl acetate (50 mL), and the organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=2:1) to yield the title compound (347.3 mg, 99%) as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].[CH3:14][C:15]([C:18]1[CH:23]=[C:22]([SH:24])[CH:21]=[C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]=1[OH:29])([CH3:17])[CH3:16].C(N(CC)CC)C.Cl>C(#N)C>[CH3:28][C:25]([C:20]1[CH:21]=[C:22]([S:24][CH2:2][C:3]([NH:5][C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:13])=[O:4])[CH:23]=[C:18]([C:15]([CH3:17])([CH3:16])[CH3:14])[C:19]=1[OH:29])([CH3:26])[CH3:27]
Reactant: Cc1cccc(C)c1NC(=O)CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(C)c1NC(=O)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by dissolving 2-chloro-N-(2,6-dimethylphenyl)acetamide (1.8 g, 0.0091 mole) and 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (2.17 g, 0.0091 mole) in acetonitrile (20 ml) under argon. Triethylamine (1.25 ml) was added and the solution stirred at room temperature under argon for 12 hours. The solution was acidified with 10% hydrochloric acid with stirring, extracted with ethyl acetate (3×), the extracts combined, washed with water and dried over sodium sulfate. The solvent was removed on a rotary evaporator and the product purified by chromatography over silica and recrystallized from ethyl acetate/benzene. m.p. ca. 137.7° C.