Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH2:19][CH:18]3[CH:15]([C:16](OC)([O:20]C)[CH2:17]3)[C:14]=2[C:24]([O:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>C(Cl)Cl.C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]2[CH2:19][CH:18]3[CH:15]([C:16](=[O:20])[CH2:17]3)[C:14]=2[C:24]([O:26][CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])(=[O:12])=[O:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COC1(OC)CC2CC(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)=C(C(=O)OC(c3ccccc3)c3ccccc3)C21
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC2CC(=O)C12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 200 mg of 3-(p-nitrophenylsulfonyl)-7,7-dimethoxybicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, in 5 mL of methylene chloride was diluted with 20 mL of acetic acid. Aqueous hydrochloric acid (4N, 3 mL) was added, the mixture was stirred for 1 hr at room temperature, and then evaporated to dryness at 25°. The residue was partitioned between methylene chloride and water and the organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was dissolved in a small amount of 5% methanol in methylene chloride and treated with an excess of diphenyldiazomethane to esterify any free acid present. After nitrogen evolution ceased, the reaction mixture was evaporated to dryness and the residue was dissolved in methylene chloride-ether to give a solution from which precipitated 127 mg (69.3%) of 3-(p-nitrophenylsulfonyl)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenyl methyl ester, as colorless crystals. IR (Nujol mull): 1730, 1780 cm-1 ; NMR (80 MHz; CDCl3): δ 2.5-3.6 (5H, m), 4.7 (1H, m), 7.0 (1H, s), 7.2-7.5 (10H, m), 8.0 (2H, d, J=9), and 8.23 (2H, d, J=9). ##STR26##
Reaction SMILES: [N:1](=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4](=O)[CH3:5])O.[CH3:13][C:14](=O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[Cl-].[NH:24]=C=O>[Zn].C(O)(=O)C>[CH3:13][C:14]1[C:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[N:24][C:4]([CH3:5])=[C:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[N:1]=1
Reactant: CCCCCCC(=NO)C(C)=O
Reactant: N=C=O
Reactant: CCCCCCCC(C)=O
Agent: [Cl-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCCCCc1nc(C)c(CCCCCC)nc1C

Procedure:
5h. 2,5-Dimethyl-3,6-dihexyl-pyrazine was prepared by first forming 3-oximino-2-nonanone by reacting 2-nonanone with nitrocyl chloride according to the method of BOUVEAULT (loc.cit.). The autocondensation of two moles of the imino-ketone in the presence of zinc and acetic acid [according to the method described in Chimia 11, 310 (1957)] yielded 2,5-dimethyl-3,6-dihexyl-pyrazine which had a b.p. of 112°-120°C./0.01 mm. Hg.
Reaction SMILES: C(N(CC)CC)C.[C:8]([OH:27])(=O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(Cl)(=O)OCC.[C:34]([OH:43])(=[O:42])[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[NH2:37]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:8]([NH:37][C:36]1[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=1[C:34]([OH:43])=[O:42])(=[O:27])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: Nc1ccccc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1ccccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.5 %

Procedure:
Triethylamine (0.46 ml) was added to a suspension of stearic acid (853 mg) in methylene chloride (8.5 ml). Then, ethyl chlorocarbonate (0.32 ml) was dropwise added to the mixture while being cooled with ice. After being stirred for 1 hour at 0° C., the mixture, with a solution of anthranilic acid (411 mg) and triethylamine (0.42 ml) in methylene chloride (2 ml) dropwise added thereto, was stirred for 16 hours at 45° C. The reaction mixture was then diluted with chloroform, washed with water and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was recrystallized from hexane-ethyl acetate mixed solution, thereby yielding 1.107 g of the aimed compound as colorless crystals. According to the comparison by using TLC and 1H-NMR, this product was identified as the aimed compound obtained by Example 1-1 (2).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[OH:7])=[O:5].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1>C(Cl)Cl>[C:18]([O:7][N:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])[C:4](=[O:5])[C:3]([CH3:17])([CH3:16])[CH2:2][Cl:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(CCl)C(=O)N(O)Cc1ccccc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(CCl)C(=O)N(Cc1ccccc1Cl)OC(=O)c1ccccc1
Temperature: 0 °C
Yield: 154 %

Procedure:
A stirred solution of 2.0 grams (0.007 mole) of 3-chloro-N-(2-chlorophenyl)methyl-N-hydroxy-2,2-dimethylpropanamide (prepared in Example 1) in 25 ml of methylene chloride was placed under an argon atmosphere and cooled to 0° C. To this was added 0.98 gram (0.007 mole) of benzoyl chloride in 5 ml of methylene chloride followed by 0.63 gram (0.008 mole) of pyridine. Upon completion of addition the reaction mixture was heated under reflux for 16 hours. The reaction mixture was diluted with methylene chloride and washed with 100 ml of water, 100 ml of aqueous 10% hydrochloric acid and finally 100 ml of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residual oil. The oil was subjected to column chromatography on silica gel. The appropriate fraction was concentrated under reduced pressure to give 4.1 grams of solid. The solid was recrystallized from ethyl acetate/cyclohexane. A precipitate was collected by filtration; mp 117°-120°. Nuclear magnetic resonance spectroscopy indicated the precipitate to be benzoic acid. The mother liquor was concentrated under reduced pressure and the residue redissolved in 60 ml of methylene chloride. The solution was washed with five portions of 20 ml each of an aqueous solution saturated with sodium bicarbonate. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give an oil residue. Volatiles were removed from the oil under reduced pressure using a short-path distilling system. There remained as a residue 1.0 gram of N-benzoyloxy-3-chloro-N-(2-chlorophenyl)methyl-2,2-dimethylpropanamide.
Reaction SMILES: [CH:1]1([CH:7]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:9]([Mg]Br)=C.[C:13]([O:21]CC)(=[O:20])[CH2:14][C:15](OCC)=O.[OH-].[K+]>C1COCC1.CCOCC>[CH:1]1(/[CH:7]=[CH:9]/[CH2:15][CH2:14][C:13]([OH:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=C[Mg]Br
Reactant: O=CC1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CC/C=C/C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of cyclohexane carboxaldehyde (11.22 g, 100 mmol, 1 equiv) in THF (100 mL) was added dropwise via addition funnel to a solution of vinylmagnesium bromide (100 mL of a 1.0 M solution in THF, 100 mmol, 1.0 equiv) in Et2O (100 mL) at 0° C. After the addition was completed, the reaction mixture was stirred for 1 h at 0° C. and then partitioned between 0.5 M HCl (150 mL) and a 1:1 mixture of EtOAc and hexanes (2×150 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford a yellow oil. This material was combined (neat) with diethyl malonate (16.7 mL, 110 mmol, 1.1 equiv) and Ti(OEt)4 (2.10 mL, 10.0 mmol, 0.10 equiv) and was heated to 160° C. for 1 h (distilling out Et2OH as it was formed). The reaction mixture was then maintained at 190° C. for 4 h and then cooled to 60° C. Et2OH (50 mL) and 6.0 M KOH (50 mL) were added sequentially, and the brown reaction mixture was refluxed for 3 h. After cooling to 23° C., the reaction mixture was filtered through a medium frit, and the filtrate was partitioned between water (150 mL) and Et2O (2×100 mL). The aqueous layer was then acidified to pH=2 (as indicated by pH paper) with concentrated HCl and extracted with a 1:1 mixture of EtOAc and hexanes (2×150 mL). The combined organic layers were dried over Na2SO4, concentrated, and the residue was distilled at reduced pressure to afford trans-5-cyclohexyl-pent-4-enoic acid (5.68 g, 31%) as a colorless liquid: bp: 150-156° C. (1 torr); IR (cm−1)3001 (br), 2923, 1711; 1H NMR (CDCl3) δ 0.96-1.32 (m, 5H), 1.60-1.76 (m, 5H), 1.85-1.94 (m, 1H), 2.27-2.44 (m, 4H), 5.31-5.48 (m, 2H); Anal. (C11H18O2) C, H.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]C(C)(C)C)=[O:8])[N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.O>ClCCl>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[NH:3]1
Reactant: CN1CCC(C(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CN1CCC(C(=O)O)N1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of bis(1,1-dimethylethyl) 2-methyl-1,5-pyrazolidinedicarboxylate dissolved in dichloromethane (DCM) (25 mL) was added TFA (30.7 mL, 398 mmol) and water (3.59 mL, 199 mmol). The reaction was stirred at rt and monitored by LCMS. When the reaction was deemed complete, the solvent was evaporated under reduced pressure to give a residue which was azeotroped from toluene (50 mL×3) in order to remove the TFA and water. The crude product was obtained as a colorless oil (97% yield based on TFA Salt), which was used directly for the next step. LC-MS (ES) m/e 130.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH2:18]=O.[CH2:20]([SH:23])[CH:21]=[CH2:22]>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[C:14]([N+:15]([O-:17])=[O:16])[CH2:18][S:23][CH2:20][CH:21]=[CH2:22])=[CH:4][CH:3]=1
Reactant: C=CCS
Reactant: C=O
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Solvent: CCO
Product: C=CCSCC(=C1NCCN1Cc1ccc(Cl)nc1)[N+](=O)[O-]
Yield: 49.3 %

Procedure:
0.5 g of 1-(6-chloro-3-pyridylmethyl)-2-nitromethyleneimidazolidine, 0.19 g of 37% formaldehyde aqueous solution and 0.22 g of allylmercaptan were added to 10 ml of ethanol, and were reacted under reflux for 2 hours. After completing the reaction, ethanol was distilled off under reduced pressure, and a small amount of ethyl acetate was added to the residue thus obtained to filter the insoluble materials out, thus obtaining 0.33 g of the aimed product (Compound No. 3) having a melting point of from 134.0° to 135.0° C.
Reaction SMILES: CO[C:3]1O[C:5](OC)=[CH:6][CH:7]=1.[NH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:29]([F:32])([F:31])[F:30])=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19]2.C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:23][N:21]1[C:22]2[C:18](=[C:17]([C:29]([F:32])([F:30])[F:31])[CH:16]=[CH:15][C:14]=2[O:13][CH2:12][CH2:11][N:10]2[CH:3]=[CH:7][CH:6]=[CH:5]2)[CH:19]=[C:20]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCN)c2n1C
Reactant: COc1ccc(OC)o1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(OCCn3cccc3)c2n1C
Temperature: 70 °C
Reaction time: 4 h
Yield: 58.5 %

Procedure:
After 1.28 g (9.69 mmol) of 2,5-dimethoxyfuran was added to a solution of 2.91 g (8.81 mmol) of ethyl 7-(2-aminoethoxy)-1-methyl-4-trifluoromethyl-2-indolecarboxylate in 30 ml of acetic acid, the mixture was stirred at 50° C. for 4 hours and at 70° C. for further an hour. Toluene was added to the reaction mixture followed by concentration under reduced pressure. Ice water was poured onto the resulting residue. The mixture was then extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography to give 1.96 g of ethyl 1-methyl-7-[2-(1H-pyrrol-1-yl)ethoxy]-4-trifluoromethyl-2-indolecarboxylate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@H:19]1[C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[C:20]1=[O:33]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@H:19]2[C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=3[CH2:23][CH2:22][N:21]([CH2:31][CH3:32])[C:20]2=[O:33])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CCN1CCc2cc(F)ccc2[C@H](N)C1=O
Product: CCN1CCc2cc(F)ccc2[C@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)C1=O

Procedure:
Following General Procedure C above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 1-(S)-amino-3-ethyl-7-fluoro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one (General Procedure 6-A), the title compound was prepared. Purification was by flash chromatography using 5% methanol/dichloromethane as the eluant.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=2)[C:14]2=[N:25][NH:26][C:27](=[O:28])[N:13]2[CH:12]=1)(C)(C)C.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]>ClCCl>[NH2:7][CH2:8]/[CH:9]=[CH:10]/[C:11]1[C:20]2[C:15](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=2)[C:14]2=[N:25][NH:26][C:27](=[O:28])[N:13]2[CH:12]=1.[C:30]([OH:36])([C:32]([F:35])([F:34])[F:33])=[O:31]
Reactant: CC(C)(C)OC(=O)NC/C=C/c1cn2c(=O)[nH]nc2c2cc3ccccc3cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC/C=C/c1cn2c(=O)[nH]nc2c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl[(2E)-3-(3-oxo-2,3-dihydrobenzo[g][1,2,4]triazolo[3,4-a]isoquinolin-6-yl)prop-2-en-1-yl]carbamate (7-7) (3.0 mg, 0.0077 mmol) in a ¼ mixture of dichloromethane and TFA (1.0 ml) was stirred at room temperature for 15 min and concentrated to dryness to give the deprotected material 7-8 as a TFA salt. LRMS m/z: found 291.1, calcd. (M+H) 291.1. 1H NMR (500 MHz, CD3OD) δ: 3.88 (d, J=6.6 Hz, 2H), 6.35 (dt, J=6.6, 15.6 Hz, 1H), 7.31 (d, J=15.7 Hz, 1H), 7.63 (s, 1H), 7.65-7.68 (m, 2H), 8.05-8.11 (m, 2H), 8.38 (s, 1H), 8.84 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=[O:13])O[C:9]2=[O:12])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:18]([NH:20][CH:21]1[CH2:23][CH2:22]1)=[O:19]>C1(C)C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7](=[O:13])[N:14]([C:15]3[CH:16]=[C:17]([CH:24]=[CH:25][C:26]=3[CH3:27])[C:18]([NH:20][CH:21]3[CH2:22][CH2:23]3)=[O:19])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Br)cc2C(=O)O1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1N1C(=O)Cc2ccc(Br)cc2C1=O
Temperature: 150 °C
Yield: 60.5 %

Procedure:
A suspension of 7-bromo-1H-isochromene-1,3(4H)-dione (1.09 g) and 3-amino-N-cyclopropyl-4-methylbenzamide (0.91 g) in a mixture of toluene (8 ml) and acetic acid (2.5 ml) was heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) at 150° C. for 60 minutes. This was process was repeated and the batches combined, diluted with ethyl acetate and washed with 1N HCl, saturated NaHCO3 solution, water, brine, dried (magnesium sulfate) to yield 3-(7-bromo-1,3-dioxo-3,4-dihydroisoquinolin-2(1H)-yl)-N-cyclopropyl-4-methylbenzamide as a brown solid (1.13 g); NMR Spectrum: (DMSOd6) 0.60 (m, 2H), 0.71 (m, 2H), 2.12 (s, 3H), 2.89 (m, 1H), 4.34 (d, 1H), 4.42 (d, 1H), 7.48 (d, 1H), 7.53 (d, 1H), 7.70 (s, 1H), 7.85 (d, 1H), 7.99 (d, 1H), 8.20 (s, 1H), 8.45 (d, 1H); Mass Spectrum: M+Na+ 435.
Reaction SMILES: [OH-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([CH3:5])[CH3:4].Cl[CH2:14][C:15]([OH:17])=[O:16].Cl>O>[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: O=C(O)CCl
Reactant: CC(C)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1ccc(OCC(=O)O)cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Into a 100 ml. flask there were placed 100 gms. sodium hydroxide in 300 ml. water and the mixture was stirred until all of the sodium hydroxide was dissolved. Without cooling, there were added 60 gms. p-isopropylphenol and 95 gms. chloroacetic acid. The mixture was stirred at a temperature between 95 and 105° C. for 1 hour and then cooled to 40° C. The reaction mixture was adjusted to a pH of approximately 2 by addition of 1 molar HCl, the mixture was cooled to room temperature and extracted with 2×300 ml. ether. Upon treatment of the ether layer with sodium carbonate solution, the sodium salt of the product precipitated. The salt was dissolved in 800 ml. water and acidified with hydrochloric acid to precipitate product. It was filtered, washed with water and dried to afford 25.6 gms. product, m.p. 84.5°-87° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:8]=[C:9]([N:11]=[N+:12]=[N-:13])[CH:10]=1)=[O:4].[C:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])(=O)[CH:22]([CH3:24])[CH3:23].CC[O-].[Na+]>CCO>[CH2:30]([O:29][C:27]([C:26]1[N:13]=[N:12][N:11]([C:9]2[CH:8]=[C:7]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=2)[C:21]=1[CH:22]([CH3:24])[CH3:23])=[O:28])[CH3:31]
Reactant: COC(=O)c1cc(N=[N+]=[N-])cc(-c2ccc(C)cc2)c1
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nnn(-c2cc(C(=O)OC)cc(-c3ccc(C)cc3)c2)c1C(C)C
Temperature: 80 °C

Procedure:
To a mixture of 5-azido-4′-methyl-biphenyl-3-carboxylic acid methyl ester (200 mg, 0.75 mmol) and ethyl isobutyrylacetate (119 mg, 0.75 mmol) in EtOH (5 mL) was added EtONa (51 mg, 0.75 mmol) and the mixture was heated to 80° C. for two hours, then cooled to room temperature. EtOH was removed from the reaction mixture to afford 5-isopropyl-1-(5-methoxycarbonyl-4′-methyl-biphenyl-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester as a gel which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:12]=[C:11]([C:21](O)=[O:22])[CH:10]=1.Cl.Cl.[NH:26]1[CH:30]=[N:29][C:28]([C@H:31]([NH2:33])[CH3:32])=[N:27]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[CH:12]=[C:11]([C:21]([NH:33][C@@H:31]([C:28]2[N:29]=[CH:30][NH:26][N:27]=2)[CH3:32])=[O:22])[CH:10]=1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(N3CCOCC3)c2)c(F)c1
Reactant: C[C@@H](N)c1nc[nH]n1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3nc[nH]n3)cc(N3CCOCC3)c2)c(F)c1
Reaction time: 16 h

Procedure:
To a solution of 2′-fluoro-4′methyl-5-morpholin-4-ylbiphenyl-3-carboxylic acid (52.0 mg, 0.15 mmol) in N,N-dimethylformamide (1.0 mL) was added (1R)-1-(1H-1,2,4-triazol-3-yl)ethanamine dihydrochloride (30.1 mg, 0.16 mmol), EDC (36.8 mg, 0.19 mmol), HOBT (22.6 mg, 0.15 mmol) and diisopropylethylamine (0.10 mL, 0.59 mmol). After 16 h, the mixture was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound. HRMS 410.1990 (M+1).). 1H NMR (500 MHz, CD3OD): δ 9.37 (s, 1H); 7.86 (d, J=7.6 Hz, 2H); 7.67 (s, 1H); 7.45 (t, J=8.1 Hz, 1H); 7.13 (d, J=7.9 Hz, 1H); 7.07 (d, J=12.0 Hz, 1H); 5.52-5.47 (m, 1H); 4.00 (t, J=4.6 Hz, 4H); 3.52 (t, J=4.5 Hz, 4H); 2.40 (s, 3H); 1.79 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:17][CH:16]=[CH:15][CH:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=O)[CH2:5]1)[CH:2]=[CH2:3].Cl.[NH2:19][OH:20].C([O-])(=[O:23])C.[Na+]>CO.C(OC(=O)C)(=O)C.N1C=CC=CC=1>[CH2:1]([C:4]1[C:5]2[O:20][N:19]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=[CH:16][C:17]=1[OH:23])[CH:2]=[CH2:3]
Reactant: CC(=O)[O-]
Reactant: C=CCC1CC=CC(C(=O)c2ccccc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: C=CCc1c(O)ccc2c(-c3ccccc3)noc12

Procedure:
A solution of 2,4-dihydrobezophenone (2.14 grams) in DMF (20 mL) was treated with potassium carbonate (1.45 grams). This mixture was heated to 40° C. and stirred for 0.5 hours. To this mixture was added allyl bromide (3.6 grams), then the reaction was stirred overnight. The mixture was diluted with ethyl acetate and washed with 1 M HCl solution and brine. The organic phase was dried over sodium sulfate and filtered. The solvent was removed in vacuo and the resulting oil was filtered through a plug of silica gel using methylene chloride and hexane (1:2) to give 4-allyloxy-2-hydroxybenzophenone. This was then dissolved in 1,2-dichlorobenzene and refluxed for 24 hours. The solvent was evaporated in vacuo and the resulting oil was filtered through a plug of silica gel using methylene chloride and hexane (1:1) to give 3-allyl-2,4-dihydrobezophenone. 3-allyl-2,4-dihydrobezophenone (1.0 grams) was dissolved in methanol (20 mL) and treated with hydroxylamine hydrochloride (1.35 grams) and sodium acetate (1.6 grams) and refluxed overnight. The solvent was evaporated in vacuo and the resulting solid was partitioned in ethyl acetate and pH 7 buffer. The organic phase was dried over sodium sulfate and filtered. The solvent was removed to give a solid. This was stirred in acetic anhydride for 2 hours and then the solvent was remove in vacuo to give an oil. The oil was dissolved in pyridine and refluxed overnight. The solvent was evaporated in vacuo and the residue was filtered through a pad of siliga gel using methylene chloride and hexane (1:1) to give 7-allyl-3-phenyl-6-hydroxybenz-[4,5]-isoxazole. To a solution of 7-allyl-3-phenyl-6-hydroxybenz-[4,5]-isoxazole (0.5 grams) in 2 mL of ethyl ether was added diazomethane (15 mL of a 0.70M soln. in Et2O) under nitrogen followed by the addition of palladium acetate (cat., 2 mg). The reaction mixture was stirred at ambient temperature for 30 min until gas evolution had ceased. The ether was evaporated in vacuo, and the residue was purified on a silica gel flash chromatography column eluted with 10% EtOAc:hexane. Evaporation of the purified fractions and solvent removal in vacuo afforded the product.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:13][CH3:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.[OH-].[Na+]>CO>[N+:15]([C:6]1[CH:7]=[C:8]([S:11][CH2:12][O:13][CH3:14])[CH:9]=[CH:10][C:5]=1[NH2:4])([O-:17])=[O:16]
Reactant: COCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCSc1ccc(N)c([N+](=O)[O-])c1

Procedure:
1.4 G. of 1 -acetamido-2-nitro-4-methoxymethylthiobenzene is treated in 6 ml. of methanol with 3 ml. of 5N aqueous sodium hydroxide solution and refluxed for 15 minutes. The solvent is removed under vacuum and the residue diluted with water and extracted with chloroform. Evaporation of the chloroform yields 2-nitro-4-methoxymethylthioaniline as reddish crystals.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1>>[CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([O:11][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(C(F)(F)F)cc1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-fluoro benzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.