Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH2:13][CH2:12][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC(=O)OCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]1([CH2:24][O:23][C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH:28]4[CH2:30][CH2:29]4)[CH:3]=3)[CH2:9][CH2:10][C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]2)[CH2:27][CH2:26]1
Reactant: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2cccc(Br)c2)CC1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C1(c2ccccc2)CCC(OCC2CC2)(c2cccc(C3CC3)c2)CC1
Temperature: 100 °C
Reaction time: 15 h
Yield: 14.5 %

Procedure:
190 mg of 4-(3-bromophenyl)-4-cyclopropylmethoxy-1-phenylcyclohexanecarboxylic acid, 57 mg of cyclopropylboronic acid, 12.4 mg of tricyclohexylphosphine, 4.97 mg of palladium(II) acetate and 376 mg of potassium phosphate (K3PO4) were heated for 4 h at 100° C. in 10 ml of toluene and 1 ml of water. The reaction mixture was allowed to stand for 15 h at room temperature and subsequently heated for a further 3 h at 100° C. It was then diluted with 50 ml of EA and washed twice with 20 ml each of a saturated aqueous sodium hydrogensulfate solution. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPLC (column: Waters X-Terra MS C18, 100×30 mm, 5 μm; eluent A: water+0.1% TFA, eluent B: acetonitrile; flow: 30 ml/min; gradient: 90% A+10% B for 2.5 min, then to 75% A+25% B in 0.5 min, then to 25% A+75% B in 11 min, then to 5% A+95% B in 1 min, then to 90% A+10% B in 2.5 min). 25 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([CH3:34])([C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])[CH3:17])=[CH:11][C:10]=1[CH3:35])[CH2:6][CH3:7])C.[OH-].[Na+]>>[CH3:35][C:10]1[CH:11]=[C:12]([O:15][C:16]([CH3:17])([C:18]2[S:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:28]=3)=[N:20][C:19]=2[CH3:33])[CH3:34])[CH:13]=[CH:14][C:9]=1[CH2:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)C(CC)Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Product: CCC(Cc1ccc(OC(C)(C)c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-2-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-benzyl)-butyric acid ethyl ester was treated with 3 N NaOH to obtain [rac]-2-(2-methyl-4-{1-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-benzyl)-butyric acid as colorless liquid.
Reaction SMILES: COC(=O)[C:4]1C=C[C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.NC1[S:35]C=CN=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[S:35][CH:4]=[CH:5][N:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: Nc1nccs1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2nccs2)cc1

Procedure:
The product from Example 1, Part C (350 mg, 1.1 mmol) and 2-aminothiazole (131 mg, 1.3 mmol) were converted to the title compound by the method described in Example 1, Part D (122 mg, 34%). 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=3.5 Hz, 1H); 7.22 (d, J=8.8 Hz, 2H); 7.02 (d, J=3.6 Hz, 1H); 7.22 (d, J=8.5 Hz, 2H); 5.11 (d, J=14.6 Hz, 1H); 4.61 (s, 1H); 4.17 (d, 14.6 Hz, 1H); 3.76 (s, 3H); 3.06 (s, 2H); 1.93 (s, 3H); 1.79 (s, 3H). MS: m/z (MH+) 404.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH:3]1[CH2:9][OH:10].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>CS(C)=O>[Cl:17][C:18]1[C:19]([O:10][CH2:9][CH:3]2[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])=[CH:20][C:21]([F:31])=[C:22]([CH:30]=1)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Reactant: CC1CCCC(C)C1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC1CCCC(C)C1COc1cc(F)c(C(=O)OC(C)(C)C)cc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
To a solution of (2,6-dimethylcyclohexyl)methanol (0.34 g, 2.40 mmol) in anhydrous dimethylsulfoxide (5 mL) were added cesium carbonate (1.56 g, 4.80 mmol) and tert-butyl 5-chloro-2,4-difluorobenzoate (0.53 g, 2.16 mmol) and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was cooled down and acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate (2×15 mL), the combined organics were washed with brine (15 mL); dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography (0 to 10% ethyl acetate in hexanes) afforded the title compound (0.43 g, 54%): MS (ES+) m/z 317.2, 315.2 (M−54); MS (ES−) m/z 315.1, 313.1, (M−56).
Reaction SMILES: C(N(CC)CC)C.O=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].Cl.[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30]N)=[CH:26][CH:25]=1.CCOCC>C(O)C>[CH3:23][C:24]1[CH:25]=[C:26]2[C:27](=[CH:28][CH:29]=1)[NH:30][C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:10]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(NN)cc1
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc2[nH]c(-c3ccccc3)c(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.1 %

Procedure:
Triethylamine (1.4 mL, 10 mmol) was added to a stirred suspension of δ-oxobenzenepentanoic acid (1.92 g, 10 mmol) and (4-methylphenyl)hydrazine hydrochloride (1.59 g, 10 mmol) in ethanol (16 mL) and the mixture was stirred at room temperature for 4 h. Ether (100 mL) was added, the mixture was filtered and the solvent was evaporated under reduced pressure. The residue was added slowly to trifluoroacetic acid (15 mL) and the mixture was heated under reflux for 2 h. The mixture was cooled, water (100 mL) was added and the mixture was extracted with ethyl acetate (100 mL). The organic fraction was washed with brine (30 mL), dried (MgSO4) and the volume was reduced to Ca. 10 mL by evaporation under reduced pressure. The precipitate was collected and recrystallized from ether to give the title compound as a pale solid (1.51 g, 54%). 1H NMR (360 MHz, DMSO-d6) δ2.39 (3H, s), 2.50-2.58 (2H, m), 3.03-3.09 (2H, m), 6.91-6.95 (1H, m), 7.23-7.25 (1H, m), 7.34-7.40 (2H, m), 7.47-7.63 (4H, m), 11.4 (1H, br s), and 12.25 (1H, br s). m/z (ES+) 280 (M+1).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:20]([OH:22])=O)=[N:11][N:12]2[CH2:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=12)C1C=CC=CC=1.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:20]([C:10]2[C:9]([OH:8])=[C:13]3[C:14](=[O:19])[NH:15][CH2:16][CH2:17][CH2:18][N:12]3[N:11]=2)=[O:22])=[CH:26][CH:25]=1
Reactant: O=C(O)c1nn2c(c1OCc1ccccc1)C(=O)NCCC2
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1nn2c(c1O)C(=O)NCCC2
Reaction time: 0.17 h

Procedure:
The title compound was prepared from 3-benzyloxy-4-oxo-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid using a procedure similar to that found in Example 13, Step 3, except that 4-fluorobenzylamine was used in place of 4-fluoro-N-methylbenzylamine and the reaction time totaled 10 minutes. Purification by reverse phase chromatography was not necessary. 1H NMR (400 MHz, CDCl3) δ 7.26-7.22 (m, 7H), 7.01-6.96 (m, 2H), 6.15 (br s, 1H), 5.30 (s, 2H), 4.57-4.55 (d, 2H), 4.46-4.43 (t, 2H), 3.16-3.11 (m, 2H), 2.20-2.13 (dt, 2H); ES MS (M+1)=409.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7].[CH:37]12[CH2:45][CH2:44][CH:41]([CH2:42][CH2:43]1)[CH2:40][NH:39][CH2:38]2.[ClH:46].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[ClH:46].[CH:37]12[CH2:45][CH2:44][CH:41]([CH2:42][CH2:43]1)[CH2:40][N:39]([C:15]([CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([C:2]([F:36])([F:35])[F:1])[CH:30]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:28]=3)[C@H:9]([CH2:18][C:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH2:10]1)=[O:17])[CH2:38]2
Reactant: C1CC2CCC1CNC2
Reactant: O=C(O)CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1)N1CC2CCC(CC2)C1
Reaction time: 6 h
Yield: 78.1 %

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(carboxymethyl)-2-(1H-indol-3-ylmethyl)piperazine (0.2 g) and 3-azabicyclo[3.2.2]nonane (0.05 g) in dry N,N-dimethylformamide (2 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.082 g) and 1-hydroxybenzotriazole (0.058 g) at room temperature. After 6 hours, the reaction mixture was poured into aqueous sodium bicarbonate solution (20 ml) and the resulting precipitate was collected by filtration. The crude product obtained was purified by column chromatography on silica gel using toluene-ethyl acetate (1:2) as an eluent and treated with 17.6% hydrogen chloride in ethanol solution to give (2R)-4-[(3-azabicyclo[3.2.2]non-3-yl) carbonylmethyl]-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)piperazine hydrochloride (0.2 g) as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[O:11])[NH:8][C:9]=1[CH:10]=[CH:16][N:17]([CH3:19])[CH3:18])(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Solvent: CO
Product: CC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture containing 35.2 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile, 300 ml of methanol and 30 ml of dimethylformamide dimethyl acetal was heated with stirring on a steam bath for 4 and 1/2 hours and then allowed to cool to room temperature. The precipitated yellow solid was collected, washed with methanol and dried in an oven under reduced pressure at 95° C. to yield 16.4 g of 5-acetyl-1,2-dihyro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridinecarbonitrile, m.p. 267°-270° C.
Reaction SMILES: C([NH:4][C:5]1(C(OCC)=O)[CH2:14][C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16])(=O)C.[ClH:22]>>[ClH:22].[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16]
Reactant: CCOC(=O)C1(NC(C)=O)Cc2cccc(C)c2NC1=O
Agent: Cl
Product: Cc1cccc2c1NC(=O)C(N)C2

Procedure:
To 2.7 g of ethyl 3-acetylamino-8-methyl-3,4-dihydrocarbostyril-3-carboxylate was added 60 ml of 20%-hydrochloric acid, then the mixture was refluxed by heating for 2 hours. The solvent was removed by evaporation, then water was removed by azetropic distillation with ethanol. The residue thus obtained was recrystallized from methanol-diethyl ether to obtain 1.74 g of 3-amino-8-methyl-3,4-dihydrocarbostyril hydrochloride. Colorless flake-like crystals. Melting point: Over 300° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H][H]>[Pd].C(O)C.O>[F:1][C:2]1[CH:30]=[C:29]([NH2:31])[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A reactor containing 4-(2-fluoro-4-nitro-phenoxy)-6-methoxy-7-(3-morpholin-4-yl propoxy)quinoline (2.5 kg) and 10 percent palladium on carbon (50 percent water wet, 250 g) in a mixture of ethanol and water containing concentrated hydrochloric acid (1.5 L) was pressurized with hydrogen gas (approximately 40 psi). The mixture was stirred at ambient temperature. When the reaction was complete (typically 2 hours), as evidenced by in process HPLC analysis, the hydrogen was vented and the reactor inerted with argon. The reaction mixture was filtered through a bed of Celite® to remove the catalyst. Potassium carbonate was added to the filtrate until the pH of the solution was approximately 10. The resulting suspension was stirred at 20 to 25° C. for approximately 1 hour. The solids were collected by filtration, washed with water, and dried at 50 to 60° C. under reduced pressure to afford the title compound (1.164 kg). 1H NMR (400 MHz, DMSO-d6): δ 8.45 (d, 1H), 7.51 (s, 1H), 7.38 (s, 1H), 7.08 (t, 1H), 6.55 (dd, 1H), 6.46 (dd, 1H), 6.39 (dd, 1H), 5.51 (br. s, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.59 (t, 4H), 2.47 (t, 2H), 2.39 (m, 4H), 1.98 (m, 2H). LC/MS Calcd for [M+H]+ 428.2. found 428.1.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[CH3:11][O-:12].[Na+]>CN(C=O)C.CO>[CH3:11][O:12][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: C[O-]
Agent: Brc1ccc2sccc2c1
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2sccc2c1
Temperature: 145 °C
Yield: 64 %

Procedure:
To a solution of 1.8 g of 5-bromobenzo[b]thiophene in 2 mL of anhydrous DMF and 1 mL of MeOH was added 686 mg of NaOMe. The mixture was heated to 110° C. (bath temp), and 121 mg of CuBr was added. The brown suspension was heated at 110° C. for ˜2 h and at ˜145° C. for 30 min. The reaction was quenched with ca. 50 mL of H2O and the mixture was extracted with 100 mL of Et2O (2×), EtOAc (1×), and CH2Cl2 (1×). The organic layers were washed with 50 mL of brine, combined, dried over MgSO4, concentrated, and flash chromatographed with 3% Et2O-hexanes to afford 894.5 mg (64%) of the title compound along with 168.8 mg (9.4%) of 5-bromobenzo[b]-thiophene.
Reaction SMILES: C([NH:14][C:15]1([CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH2:20]1)[CH2:16][P:17]([OH:19])[OH:18])(C1C=CC=CC=1)C1C=CC=CC=1.C(NC(P(O)O)C(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[NH2:14][C:15]1([CH2:16][P:17]([OH:19])[OH:18])[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH2:24]1
Reactant: OP(O)CC1(NC(c2ccccc2)c2ccccc2)C=CC(Cl)=CC1
Agent: CC(C)C(NC(c1ccccc1)c1ccccc1)P(O)O
Product: NC1(CP(O)O)C=CC(Cl)=CC1

Procedure:
The procedure described in Example 1C was repeated using DL-1-benzhydrylamino-p-chlorobenzylphosphonous acid as starting material instead of DL-1-benzhydrylamino-2-methylpropanephosphonous acid to give DL-1-amino-p-chlorophenylmethanephosphonous acid of melting point 228°-230° (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:10]2[CH2:11][C:12]3[C:17]([CH:9]12)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:24]2[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:18]1([C:24]2[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=2)[O:30][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1C2Cc3ccccc3C21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1Cc2ccccc2[C@H]1Oc1cccc(-c2ccccc2)c1
Yield: 35.2 %

Procedure:
A solution of (±) N-tert-butoxycarbonyl-1,2-iminoindane (5 g, 22 mmol), 3-phenylphenol (3.75 g, 22 mmol) and pyridinium p-toluenesulfonate (114 mg) in chloroform (150 ml) was heated at reflux for 2 h. On cooling, the solution was washed sequentially with 10% aq. NaOH, water and then brine. After drying over MgSO4, solvents were removed in vacuo and the resultant brown oil subjected to column chromatography on silica gel eluting with 20% diethyl ether in hexanes to afford the title compound (3.11 g).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([CH3:13])[N:9]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[NH:5][C:6]=1I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C.O>[I:1][C:2]1[NH:3][C:4]([C@@H:8]2[CH2:12][CH2:11][C@H:10]([CH3:13])[N:9]2[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])=[N:5][CH:6]=1
Reactant: C[C@H]1CC[C@@H](c2nc(I)c(I)[nH]2)N1C(=O)OC(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@@H](c2ncc(I)[nH]2)N1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-(4,5-diiodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (4.28 g, 8.50 mmol) in ethanol (75 mL) and water (75 mL), sodium thiosulfate (10.72 g, 85.1 mmol) was added and the reaction mixture was stirred vigorously for 1 hour at 100° C., 16 hours at 90° C., and 5 hours at 100° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed additionally with ethyl acetate and the organic layers were combined. The organic layer was dried with sodium sulfate, concentrated and the crude material was purified by column chromatography to yield (2S,5S)-tert-butyl 2-(5-iodo-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate as a white solid (2.34 g, 6.20 mmol, 73%). 1H NMR (400 MHz, cdcl3) δ 7.04 (s, 1H), 4.89 (dd, 1H), 3.92 (m, 1H), 2.91 (s, 1H), 2.18-2.06 (m, 2H), 1.78 (m, 1H), 1.52 (m, 1H), 1.48 (s, 9H), 1.13 (d, 3H).
Reaction SMILES: C(O[C:4](=[O:30])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15]([F:29])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:9][N:8]=1)C.ClC(=O)[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[CH2:36]([O:35][C:33](=[O:34])[C:4]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[C:15]([F:29])=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:9][N:8]=1)=[O:30])[CH3:37]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCOC(=O)NCc1ccc(Cc2ccc(OC)c(-c3cccc(Cl)c3)c2F)cn1
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCc1ccc(Cc2ccc(OC)c(-c3cccc(Cl)c3)c2F)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35.1 %

Procedure:
Into a 20 mL vial was added [5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-carbamic acid ethyl ester (P-367) (152 mg, 0.43 mmol), dichloromethane (4 mL), TEA (0.11 mL, 0.85 mmol). The solution was cooled to 0° C. and Ethyl chlorooxoacetate (71 uL, 0.64 mmol) was added. After 20 minutes at room temperature, the organic solution was washed with H2O and brine, and then concentrated. Ethyl acetate was added to the residue, which produced a solid and was filtered. The solid was triturated with ether and dried to give N-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylmethyl]-oxalamic acid ethyl ester (I-40) (69 mg, 35%) as a gray-blue solid.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:3]=1[C:4]([N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[C:24]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)=[CH:28][CH:27]=1)#[N:25]>CN(C)C=O>[C:24]([C:26]1[CH:38]=[CH:37][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:17][C:15]2[CH:14]=[CH:13][C:3]([C:4]([N:6]([CH:10]([CH3:11])[CH3:12])[CH:7]([CH3:8])[CH3:9])=[O:5])=[C:2]([OH:1])[CH:16]=2)=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1ccc(OCCCCCBr)cc1
Reactant: CC(C)N(C(=O)c1ccc(O)cc1O)C(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1O)C(C)C
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A solution of 2,4-dihydroxy-N,N-bis(1-methylethyl)benzamide (3 g, 12.7 mmol) in 30 mL of N,N-dimethylformamide is treated with cesium carbonate (4.97 g, 15.2 mmol), and 5-(4-cyanophenoxy)pentyl bromide (3.4 g, 12.7 mmol) and stirred at 40° C. for 24 hours. The reaction is partitioned between ethyl acetate and water, dried over sodium sulfate and concentrated in vacuo to afford a yellow foam. This material is purified by chromatography on silica gel (30 g) with 30-70% ethyl acetate/hexane as the eluent to afford 4-[5-(4-cyanophenoxy)pentyloxy]-2-hydroxy-N,N-bis(1-methylethyl)benzamide as colorless foam.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][Si:13]([CH3:24])([CH3:23])[C:14]1[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH2:21][OH:22])[CH:18]=1>C(Cl)Cl>[CH3:24][Si:13]([CH3:12])([CH3:23])[C:14]1[O:15][CH:16]=[C:17]([CH2:19][CH2:20][CH:21]=[O:22])[CH:18]=1
Reactant: C[Si](C)(C)c1cc(CCCO)co1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[Si](C)(C)c1cc(CCC=O)co1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring mixture of pyridinium chlorochromate (3.89 g, 18.03 mmol) suspended in methylene chloride (100 ml) at 0 degrees was added 3-(2-trimethylsilyl-4-furyl)propan-1-ol (1.19 g, 6.01 mmol), prepared as in Example 2, in dry methylene chloride (15 ml). This mixture was allowed to warm to room temperature, stirred for 90 minutes, filtered and concentrated to give the desired aldehyde.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[C:3]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)=[N:4][OH:5].C[Si]([N:26]=[C:27]=[O:28])(C)C.N1C=CC=CC=1>C1COCC1>[C:27]([O:5][N:4]=[C:3]([C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=12)[CH:2]([CH3:21])[CH3:1])(=[O:28])[NH2:26]
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)C(=NO)c1c(-c2ccccc2)nn2ccccc12
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)C(=NOC(N)=O)c1c(-c2ccccc2)nn2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 630 mg (2.24 mmol) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one oxime in 2 ml of anhydrous THF was added 600 μl of trimethylsilyl isocyanate (85%) dropwise at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight, followed by the addition of 500 μl pyridine and stirring for another 4 hours. The solvent was removed in vacuo, and the residue obtained was purified on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant to yield 482 mg (66.3%) of 2-methyl-1-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one O-carbamoyl oxime. Compound 1017.