Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[C:19]3[CH:20]=[C:21]([C:25]4[N:29]=[CH:28][O:27][N:26]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:37][N:38](C=O)C.O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([C@@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]3[N:29]=[CH:28][O:27][N:26]=3)[CH:20]=2)[N:16]2[CH2:15][CH:14]([C@@H:9]([C:4]3[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=3)[C:37]#[N:38])[C:10]([F:13])([CH3:12])[CH3:11])[CH2:17]2)=[CH:31][CH:32]=1
Reactant: CN(C)C=O
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(-c3ncon3)c2)C1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CC(C)(F)[C@H](c1cc(F)cc(C#N)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(-c3ncon3)c2)C1
Temperature: 135 °C
Reaction time: 14 h

Procedure:
A mixture of 60 mg (0.104 mmol) of 3-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methyl propyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,2,4-oxadiazole, 48.5 mg (0.84 mmol) of zinc cyanide, 4 mg (0.004 mmol) of tris(dibenzylideneacetone)-dipalladium, and 5 mg (0.009 mmol) of DPPF in 3 mL of DMF/H2O (99/1) was degassed with N2 for 1 h at rt. Then it was stirred at 135° C. After 14 h, the reaction mixture was concentrated to remove solvents. Then the mixture was poured into 20 mL of CH2Cl2 and 5 mL of aq NaHCO3 (pH>7). The aqueous layer was extracted with CH2Cl2 and the combined organic layer was dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography with hexanes/acetone to afford the title compound as a white solid; Mass Spectrum: m/e=519 (M+1, 35Cl), 521 (M+1, 37Cl).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[F:18][C:19]([F:37])([F:36])[C:20]([C:23]1[CH:32]=[CH:31][C:30]2[CH2:29][C@@H:28]([C:33](O)=[O:34])[CH2:27][CH2:26][C:25]=2[N:24]=1)([CH3:22])[CH3:21].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>CN1CCCC1=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:33]([C@H:28]1[CH2:27][CH2:26][C:25]2[N:24]=[C:23]([C:20]([CH3:22])([CH3:21])[C:19]([F:37])([F:36])[F:18])[CH:32]=[CH:31][C:30]=2[CH2:29]1)=[O:34])[CH3:4]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: CC(C)(c1ccc2c(n1)CC[C@H](C(=O)O)C2)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc([C@@H](C)NC(=O)[C@H]2CCc3nc(C(C)(C)C(F)(F)F)ccc3C2)c(F)cc1NS(C)(=O)=O
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A 2 ml, vial was charged with (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (51 mg, 0.18 mmol), (S)-2-(1,1,1-trifluoro-2-methylpropan-2-yl)-5,6,7,8-tetrahydroquinoline-6-carboxylic acid (47 mg, 0.16 mmol) and N,N-diisopropylethylamine (110 uL, 0.65 mmol) and N-methylpyrrolidinone (0.8 mL). A solution of N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (75 mg, 0.20 mmol) in N-methylpyrrolidinone (0.4 mL) was added and the resulting mixture was stirred at room temperature. After 30 min the mixture was filtered and purified by reverse-phase HPLC (10-75% MeCN in 10 mM Et2NH/H2O) to afford the amide as a solid (72 mg, 85%). The sample was dissolved in hot 2/3 IPA/hexane (5 mL). 1.2 mL injections were separated on a ChiralPak AD-H 5 um, 250×20 mm column, eluting with 85/15/0.03 hexane/IPA/Et2NH at 20 mL/min. Peaks eluted at 7.5 and 8.7 min, with UV monitoring at 254 and 230 nm. The major isomer, eluting at 8.7 min was concentrated to afford the amide as fine plates (47 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.41 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.07 (d, J=11.6 Hz, 1H), 5.09 (app pentet, J=7.2 Hz, 1H), 3.01 (s, 3H), 2.92-2.78 (m, 4H), 2.71-2.61 (m, 1H), 2.26 (s, 3H), 2.06-1.97 (m, 1H), 1.82-1.69 (m, 1H), 1.53 (s, 3H), 1.35 (d, J=7.1 Hz, 3H); m/z=516.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[K])(C)(C)C.O>CN1C(=O)CCC1>[CH2:11]([O:18][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccnc(OCc2ccccc2)c1
Temperature: 125 °C
Reaction time: 6 h
Yield: 71.3 %

Procedure:
2-Chloro isonicotinic acid (9.45 g) and benzyl alcohol (12.977 g) were dissolved in NMP (180 mL), and treated with tBuOK (20.2 g) between 10-25° C. The reaction mixture was then stirred at 125° C. (Bath-temperature) for 6 h, cooled down to r.t., poured into water (1500 ml) and extracted twice with water. The combined aqueous phases were treated with concentrated aqueous HCl until pH 3 (16 ml). After 10 min the solid was filtered, washed with water and dried under high vacuum, to give the title compound as an off-white solid (9.8 g). MS (m/e)=228.1 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:5]2[N:6]=[C:7]([CH3:31])[C:8]([C@H:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:9]([C:10]3[C:11]([CH3:21])=[C:12]4[C:17](=[C:18]([F:20])[CH:19]=3)[O:16][CH2:15][CH2:14][CH2:13]4)[N:4]2[N:3]=1.NC1C=C2N=C(C)C(C(OC(C)(C)C)C(O)=O)=C(C3[C:43]([CH3:53])=[C:44]4[C:49](=[C:50](F)C=3)[O:48][CH2:47][CH2:46][CH2:45]4)N2N=1.C1(CCC(Cl)=O)CCCC1.CCN(C(C)C)C(C)C>C1COCC1>[C:27]([O:26][C@@H:22]([C:8]1[C:7]([CH3:31])=[N:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:47](=[O:48])[CH2:46][CH2:45][CH:44]3[CH2:43][CH2:53][CH2:50][CH2:49]3)[CH:32]=2)[C:9]=1[C:10]1[C:11]([CH3:21])=[C:12]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][CH2:15][CH2:14][CH2:13]2)[C:23]([OH:25])=[O:24])([CH3:28])([CH3:29])[CH3:30]
Reactant: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1C(OC(C)(C)C)C(=O)O
Agent: O=C(Cl)CCC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc2cc(NC(=O)CCC3CCCC3)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A mixture of 2S)-2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (22 mg, 0.050 mmol), 3-cyclopentylpropanoyl chloride (8.79 mg, 0.055 mmol), Hunig's Base (0.026 mL, 0.15 mmol) in THF (2 mL) was stirred at rt for 16 h. It was then concentrated in vacuo and purified by prep HPLC (TFA/MeOH), the desired fractions were combined and adjusted to pH=6 using a few drops of 1N NaOH. The residue was then acidified to pH=4 using a few drops of 1N HCl. This solution was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain (10 mg, 35%) of (2S)-2-tert-butoxy-2-(2-(3-cyclopentylpropanamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid as white solid.
Reaction SMILES: [P:1]([O-:15])([O:9]CC(C)(C)C)[O:2]C1C=CC=CC=1.[CH3:16][C:17]1[C:22]([OH:23])=[C:21]([CH3:24])[C:20]([CH3:25])=[C:19]([C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)([CH3:28])[CH3:27])[C:18]=1[CH3:36].C[O-].[Na+]>>[CH2:19]([PH:1]([OH:15])([OH:9])[OH:2])[C:26]([CH3:29])([CH3:28])[CH3:27].[CH2:19]([PH:1]([OH:15])([OH:9])[OH:2])[C:26]([CH3:29])([CH3:28])[CH3:27].[CH3:24][C:21]1[C:22]([OH:23])=[C:17]([CH3:16])[C:18]([CH3:36])=[C:19]([C:26]([C:29]2[CH:30]=[CH:31][C:32]([OH:35])=[CH:33][CH:34]=2)([CH3:28])[CH3:27])[C:20]=1[CH3:25]
Reactant: CC(C)(C)COP([O-])Oc1ccccc1
Agent: C[O-]
Agent: Cc1c(C)c(C(C)(C)c2ccc(O)cc2)c(C)c(C)c1O
Agent: [Na+]
Product: CC(C)(C)C[PH](O)(O)O
Temperature: 130 °C

Procedure:
A mixture of 216 g (0.95 mole) of phenyl neopentyl phosphite, 134 g (0.47 mole) of tetramethyl-bisphenol-A, and 1 g of sodium methoxide were heated together in a round-bottom flask. The temperature of the reaction vessel was raised to 130° C. and a vacuum was applied. Phenol was distilled over a head temperature of 90° C. at 35 mm Hg. The temperature was raised slowly to 160° C. and the vacuum increased to 0.2 mm Hg to remove any phenol and unreacted phenyl neopentyl phosphite. The proton NMR spectrum of the product obtained showed the methyl protons at 0.77, 1.30, 1.60, 2.17 and 2.27 δ (30.8 hydrogens), the methylene protons at 3.37 and 4.43 δ (7.1 hydrogens), and the aromatic protons at 6.83 δ (4.2 hydrogens). This bisphosphite had the following structure: ##STR4##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O.C(N(CC)CC)C>C(Cl)Cl.CC#N.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:26])[C@H:9]1[C@H:14]([OH:15])[CH2:13][CH2:12][N:11]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of trans(+/−)-benzyl 3-(tert-butoxycarbonylamino)-4-hydroxypiperidine-1-carboxylate (1.0 equiv.) in DCM and CH3CN (1:1, 0.14 M) was added BOC2O (1.0 equiv.), triethylamine (1.5 equiv.), and DMAP (catalytic amount). The reaction was stirred at room temperature for 15 h, upon which time the solution was concentrated and purified via silica gel column chromatography eluting with EtOAc and hexanes (1:6) to give the desired product as a white foam. LCMS (m/z): 451.1 (MH+).
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]2[CH:9]=[C:10]([O:14]C(=O)C)[CH:11]=[CH:12][CH:13]=2)=[N:5][C:4]2[CH:18]=[CH:19][S:20][C:3]1=2.P(Br)(Br)([Br:23])=O.C([O-])([O-])=O.[K+].[K+].Cl>CC#N.O>[Br:23][C:2]1[C:3]2[S:20][CH:19]=[CH:18][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(=O)Oc1cccc(-c2nc3ccsc3c(=O)[nH]2)c1
Reactant: O=P(Br)(Br)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Oc1cccc(-c2nc(Br)c3sccc3n2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred mixture of acetic acid 3-(4-oxo-3,4-dihydro-thieno[3,2-d]pyrimidin-2-yl)-phenyl ester, 27, (1.72 g, 6.0 mmol) in MeCN (25 mL) under a nitrogen atmosphere was added POBr3 (8.6 g, 30 mmol) and the resulting mixture was heated at reflux for 2.5 h. The reaction mixture was quenched by pouring onto iced water (200 mL) and the aqueous layer was neutralized by addition of solid NaHCO3. The precipitate formed was collected by filtration and dried. The resulting tan solid (1.6 g) was dissolved in THF/MeOH (1:1 v/v, 20 mL). K2CO3 (1.76 g, 12.8 mmol) was added and the mixture stirred at rt for 3.5 h. The reaction mixture was diluted with H2O (20 mL), acidified to pH 3-4 with 2M HCl and extracted with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), concentrated and purified by flash chromatography (70:30 hexanes/EtOAc as eluent) to afford the title compound, IVa, as a colourless solid (0.76 g; 41%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH:13]3[CH2:26][C:15]4([CH2:18][N:17]([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:16]4)[CH2:14]3)[CH:12]=2)=[CH:4][C:3]=1[O:27][CH:28]([C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=1[Cl:38])[CH3:29].C1(C)C=CC=CC=1>C(O)=O>[CH:19]([OH:21])=[O:20].[CH2:16]1[C:15]2([CH2:14][CH:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:4]=[C:3]([O:27][CH:28]([C:30]5[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=5[Cl:38])[CH3:29])[C:2]([NH2:1])=[N:7][CH:6]=4)[CH:9]=[N:10]3)[CH2:26]2)[CH2:18][NH:17]1
Reactant: CC(Oc1cc(-c2cnn(C3CC4(C3)CN(C(=O)OC(C)(C)C)C4)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CC(Oc1cc(-c2cnn(C3CC4(CNC4)C3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.7 %

Procedure:
tert-Butyl 6-(4-(6-amino-5-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (53 mg, 0.094 mmol) was dissolved in formic acid (3 mL). The solution was sonicated at room temperature for 1.0 h and then concentrated by evaporation in vacuo to give the residue. Toluene (2×5 mL) was added and evaporated again. Ether (10 mL) was added and the mixture was stirred at room temperature for 1.0 h. The solid was collected by filtration, washed with ether (10 mL) and then dried under high vacuum to afford (±)-5-(1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)pyridin-2-amine formate (29 mg, 61%) as an off-white solid.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH:21]=O.C(O)(=O)C>CO>[CH2:5]([O:8][C:9]([C:11]1[N:12]([NH:16][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([F:26])=[C:18]([Cl:17])[CH:19]=2)[CH:13]=[CH:14][CH:15]=1)=[O:10])[CH:6]=[CH2:7]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: C=CCOC(=O)c1cccn1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCOC(=O)c1cccn1NCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.4 %

Procedure:
Sodium cyanoborohydride (1.11 g, 16.8 mmol) was added to a solution of 1-amino-1H-pyrrole-2-carboxylic acid allyl ester (Example 1b, 1.12 g, 6.74 mmol), 3-chloro-4-fluorobenzaldehyde (1.32 g, 8.08 mmol) and acetic acid (1.2 mL), in methanol (50 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, quenched with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate (2×50 mL). The organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (Teledyne Isco RediSep 40 g, 0→40% ethyl acetate in hexanes) afforded the desired product, 1-(3-chloro-4-fluoro-benzylamino)-1H-pyrrole-2-carboxylic acid allyl ester (1.36 g, 4.41 mmol, 65% yield) as an off-white oil. 1H NMR (400 MHz, CDCl3) δ 4.06 (2H, d, J=5.5 Hz), 4.76 (2H, d, J=5.3 Hz), 5.29 (1H, d, J=11.0 Hz), 5.40 (1H, d, J=16.4 Hz), 5.96-6.05 (2H, m), 6.58 (1H, t, J=5.5 Hz), 6.76 1H, (t, J=1.9 Hz), 6.91 (1H, dd, J1=4.3 Hz, J2=1.8 Hz), 7.06 (1H, t, J=8.6 Hz), 7.10-7.14 (1H, m), 7.33 (1H, dd, J1=7.1 Hz, J2=1.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:5]([O:21][CH2:22][C:23]([O:25]C)=[O:24])[C:4]=1[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30].[OH-].[K+].Cl>CO>[C:23]([CH2:22][O:21][C:5]1[C:4]([CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[C:9](=[O:20])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([OH:25])=[O:24]
Reactant: COC(=O)COc1c(C(=O)CCc2ccc(OC)cc2)ccc(OC)c1CCC(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCC(=O)c2ccc(OC)c(CCC(C)C)c2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Then, 14.2 g of 1-(4-methoxy-2-methoxycarbonylmethoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone was dissolved in 80 ml of methanol, and 100 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 30 minutes. After the reaction, the reaction mixture was made acidic by dilute hydrochloric acid and extracted with diethyl ether. The solvent was removed from the diethyl ether layer by distillation to obtain 13.1 g (yield=95.3%) of 1-(carboxymethoxy-4-methoxy-3-isopentylphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:26])[C:22]([O:24]C)=[O:23]>CO.[OH-].[Na+]>[CH2:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4](=[O:27])[C:3]([OH:28])=[O:2])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21](=[O:26])[C:22]([OH:24])=[O:23]
Reactant: COC(=O)C(=O)c1ccccc1OCCOc1ccccc1C(=O)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccccc1OCCOc1ccccc1C(=O)C(=O)O

Procedure:
A mixture of 4,4'-[1,2-ethanediylbis(oxy)bis(alpha-oxobenzeneacetic acid) dimethyl ester (4:1) molar hydrate (0.385 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19. Extraction with tetrahydrofuran provided solids where were crystallized from acetonitrile to give 0.315 g of colorless 4,4'-[1,2-ethanediylbis(oxy) bis(alpha-oxobenzene-acetic acid) acid as an 0.25 molar hydrate, mp 212°-213° C.
Reaction SMILES: C(O[C:4](=[O:20])[CH2:5][C:6](=O)[CH2:7][CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)C.[NH2:21][C:22]1[CH:26]=[CH:25][NH:24][N:23]=1>CCO>[OH:20][C:4]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[N:21]=[C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13]2)[CH:5]=1
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)CC1CCC(C(=O)OCC)CC1
Solvent: CCO
Product: CCOC(=O)C1CCC(Cc2cc(O)n3nccc3n2)CC1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a 50 mL round-bottom flask containing ethyl 4-(4-ethoxy-2,4-dioxobutyl)cyclohexanecarboxylate (Int-4e, 2.33 g, 8.19 mmol) was added 3-amino-1H-pyrazole (681 mg, 8.19 mmol). The flask was heated via heat gun to ensure mixing of the oils, and then the reaction was shaken at 100° C. for 18 hours. After 18 hours, the resulting solid was taken up in EtOH and then the solvent was removed in vacuo to dry product. The product was then pumped dry on high vacuum overnight to further dry the product. The compound was taken on without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([CH:12]([F:14])[F:13])=[CH:10][C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:8][C:7]=12)#[CH:2].Br[C:26]1[S:30][C:29]([S:31]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)(=[O:33])=[O:32])=[CH:28][CH:27]=1>>[F:13][CH:12]([F:14])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:26]3[S:30][C:29]([S:31]([N:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)(=[O:32])=[O:33])=[CH:28][CH:27]=3)=[C:7]2[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)s2)CC1

Procedure:
The title compound was prepared from 3-ethynyl-7-difluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.15) (169 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (220 mg, 76%). MS (EI) 581.1 [(M)+]; mp 214° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]([S:14]([CH3:17])(=[O:16])=[O:15])S(C)(=O)=O)[C:5]([CH3:8])=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+].[C:66](=[NH:79])([C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1)[C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[C:67]1([C:66](=[N:79][C:2]2[CH:3]=[C:4]([NH:9][S:14]([CH3:17])(=[O:16])=[O:15])[C:5]([CH3:8])=[N:6][CH:7]=2)[C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: Cc1ncc(Br)cc1N(S(C)(=O)=O)S(C)(=O)=O
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Product: Cc1ncc(N=C(c2ccccc2)c2ccccc2)cc1NS(C)(=O)=O
Temperature: 130 °C

Procedure:
To two 20 mL microwave vials were added N-(5-bromo-2-methylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (1.300 g, 3.79 mmol) (780 mg each), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Acros) (0.219 g, 0.379 mmol) (121 mg each), tris(dibenzylideneacetone)dipalladium (o) (Strem) (0.173 g, 0.189 mmol) (104 mg each), sodium tert-butoxide (Fluka) (1.092 g, 11.36 mmol) (655 mg), DMF (12 mL each vial), and benzophenone imine (Aldrich) (0.699 mL, 4.17 mmol) (0.420 mL each). Both resulting mixtures were degassed by bubbling N2 for 5 min then sealed off and microwave heated at 130° C. for 20 min. LC/MS showed no sign of starting material mass with desired product mass as the major peak on both vials. Both reaction mixtures were combined and partitioned between EtOAc and sat. NH4Cl. The aqueous layer was extracted with EtOAc (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 20% to 40% acetone in hexanes) to afford the desired product as a yellow foam-like solid (430 mg). MS (ESI pos. ion) m/z: 365.8. 1H NMR (300 MHz, CDCl3) δ ppm 2.43 (s, 3H) 2.75 (s, 3H) 6.07 (br. s., 1H) 7.09-7.21 (m, 3H) 7.29-7.37 (m, 3H) 7.38-7.47 (m, 2H) 7.48-7.56 (m, 1H) 7.75 (d, J=7.02 Hz, 2H) 7.92 (d, J=2.19 Hz, 1H).
Reaction SMILES: Cl[C:2](OCC)=O.[OH-].[Na+].[CH3:9][NH:10][CH2:11][CH:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:15]=1)[OH:13]>O.C(Cl)(Cl)Cl>[CH3:9][N:10]([CH3:2])[CH2:11][CH:12]([C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2([CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:15]=1)[OH:13]
Reactant: CNCC(O)C1=CC2(CCCC2)c2ccccc21
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CC(O)C1=CC2(CCCC2)c2ccccc21
Temperature: 10 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (0.7 g) and sodium hydroxide (0.3 g) dissolved in water (10 ml) are added to 2-methylamino-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]-ethanol (1.3 g) in chloroform (25 ml). The mixture is stirred vigorously for 2 hours at about 10° C. The chloroform layer is separated, washed with water and dried. The solvent is removed in vacuo and the residual crude 2-(N-ethoxycarbonyl-N-methylamino)-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol is dissolved in tetrahydrofuran (75 ml) and added to lithium aluminium hydride (2.0 g) in tetrahydrofuran (25 ml). The mixture is refluxed for 3 hours, and the excess of hydride is destroyed with a slight excess of saturated aqueous sodium sulphate solution. The inorganic salt precipitate is filtered off and washed with tetrahydrofuran. The combined filtrate and washings are dried over sodium sulphate and the solvent is removed under reduced pressure. The crude title compound is dissolved in acetonitrile and treated with a slight excess of oxalic acid dissolved in acetonitrile. The slowly depositing hydrogen oxalate is collected by filtration and recrystallization from acetonitrile; m.p. 133°-134° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=O)[C:5]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2.C(C1N2C(C=CC=C2)=C(C(OCC)=O)C=1)(=O)C.C(Cl)(=O)C([Cl:35])=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]([Cl:35])=[O:14])[C:5]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)c2cccccc1-2
Agent: CCOC(=O)c1cc(C(C)=O)n2ccccc12
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)c2cccccc1-2

Procedure:
3-Methyl azulene-1-carbonyl chloride was prepared in situ from 3-methyl azulene-1-carboxylic acid (R. N. McDonald et al., J. Org. Chem., 41, 1822 [1976] by addition of one equivalent of oxalyl chloride to a solution of the acid in dichloromethane.