Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[C:7](=[CH2:17])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=O)[CH2:11][C:5]=2[CH:4]=1.Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]2[C:7](=[CH2:17])[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[N:21][OH:22])[CH2:11][C:5]=2[CH:4]=1
Reactant: NO
Reactant: C=C1c2ccc(OC)cc2CC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C1c2ccc(OC)cc2CC(=NO)c2ccccc21
Yield: 98.1 %

Procedure:
A solution of 2-methoxy-5-methylene-10-oxo-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (9.7 g, 0.0388 mol), hydroxylamine hydrochloride (3.42 g, 0.0492 mol), and sodium acetate (4.26 g, 0.0519 mol) in methanol (194 ml) is heated under reflux for 2 hours. The solvent is removed under reduced pressure, the residue is slurried in water (200 ml), the pH is adjusted to 8 with concentrated aqueous ammonia, and the slurry is extracted with ether (3×105 ml). The combined extracts are dried over MgSO4 and filtered, and the filtrate is evaporated to yield 10.1 g (98%) of crude material. A sample recrystallized from ether has m.p. 125°-127° C.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:21])([F:20])[C:8]([NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:9]>>[F:6][C:7]([F:20])([F:21])[C:8]([NH:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:17]=2)[CH2:12]1)=[O:9]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(NC1Cc2ccccc2C1)C(F)(F)F
Product: O=C(NC1Cc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Temperature: 25 °C
Yield: 71 %

Procedure:
After cooling chlorosulfonic acid (3.0 ml) to −78° C. under nitrogen, 2,2,2-trifluoro-N-(2,3-dihydro-1H-inden-2-yl)acetamide (500.0 mg, 2.2 mmol) was added and then allowed to warm up to rt. The solution was poured into an ice-water mixture (100.0 ml), followed by an extraction with EtOAc. The organic layer was dried over MgSO4 and evaporated in vacuo. The residue was triturated with Et2O to obtain the product as a white solid (510.0 mg, 71% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.93-7.91 (m, 2H), 7.51-7.49 (m, 1H), 6.50 (s, 1H), 4.91-4.83 (m, 1H), 3.52 (dd, J=16.8, 7.3 Hz, 2H), 3.05 (dd, J=17.0, 4.8 Hz, 2H).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH:8]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:4][N:3]=1.[CH3:17][CH2:18][CH2:19][CH2:20][CH:21]([C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)[CH2:22][CH2:23][CH2:24][CH3:25].[NH2-].[Na+]>>[CH3:12][CH2:11][CH2:10][CH2:9][CH:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:28]2[CH:27]=[C:26]([CH:21]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:20][CH2:19][CH2:18][CH3:17])[CH:31]=[CH:30][N:29]=2)[CH:7]=1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCC(CCCC)c1ccnc(N)c1
Reactant: CCCCC(CCCC)c1ccncc1
Agent: [NH2-]
Agent: [Na+]
Product: CCCCC(CCCC)c1ccnc(-c2cc(C(CCCC)CCCC)ccn2)c1

Procedure:
A mixture of 50.7 g (1.3 moles) of sodamide preformed in situ as in Example 1, 350 cc of xylene containing 0.1 cc of oleic acid, and 205 g (1 mole) of 4-(5-nonyl)pyridine was placed in a Magne Drive such as the one described in Example 2. The autoclave was closed and purged of air with nitrogen, pressurized to 10 psig with ammonia and 200 psig with nitrogen. The pressure relief valve was set at 350 psig. The mixture was heated to 173° C. at which temperature amination began. The temperature was reduced and the reaction was run at 158°-163 ° C. for 8.7 hours. Hydrogen was evolved during this time. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 150 cc of water. The xylene phase was separated and the bottom aqueous caustic phase was re-extracted with 25 cc of xylene. Both xylene extracts were combined and distilled to give 2-amino-4-(5-nonyl)pyridine boiling at 197°-225 ° C. at 22 mm Hg. The yield was 67.3%. This result substantially increases the yield of 2-amino-4-(5-nonyl)pyridine over that reported previously by one of the applicants, McGill, U.S. Pat. No. 4,177,349 (1979) and McGill, U.S. Pat. No. 4,267,335 (1981). In this prior work, 4-(5-nonyl)pyridine was shown to prefer to couple in the presence of sodamide, giving high yields of 4,4'-di-(5-nonyl)-2,2'-bipyridyl but only low yields of 2-amino-4-(5-nonyl)pyridine. This increased yield of 2-amino-4 (5-nonyl)pyridine is of importance because the compound has valuable biocidal properties.
Reaction SMILES: C1(CCO)CC1.[CH3:7][C@H:8]1[C@H:13]([OH:14])[CH2:12][C@@H:11]2[CH2:15][C@H:9]1[C:10]2([CH3:17])[CH3:16].FC1C=C(F)C(F)=CC=1C(NS(C)(=O)=O)=O.[Cl:34][C:35]1[C:36](F)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[O:41]>>[Cl:34][C:35]1[C:36]([O:14][C@@H:13]2[CH2:12][C@@H:11]3[CH2:15][C@@H:9]([C:10]3([CH3:16])[CH3:17])[C@H:8]2[CH3:7])=[CH:37][C:38]([F:48])=[C:39]([CH:47]=1)[C:40]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])=[O:41]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Reactant: C[C@H]1[C@H](O)C[C@@H]2C[C@H]1C2(C)C
Agent: CS(=O)(=O)NC(=O)c1cc(F)c(F)cc1F
Agent: OCCC1CC1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Oc1cc(F)c(C(=O)NS(C)(=O)=O)cc1Cl)C2(C)C

Procedure:
Following the procedure as described in Example 1 and making variations as required to replace 2-cyclopropylethanol with (1R,2R,3R,5S)-2,6,6-trimethylbicyclo-[3.1.1]heptan-3-ol and 2,4,5-trifluoro-N-(methylsulfonyl)benzamide with 5-chloro-2,4-difluoro-N-(methylsulfonyl)-benzamide, the title compound was obtained as a colorless solid (0.06 g, 5%): 1H NMR (300 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.74 (d, J=7.5 Hz, 1H), 7.33 (d, JC-F=12.6 Hz, 1H), 4.79-4.74 (m, 1H), 3.31 (s, 3H), 2.71-2.64 (m, 1H), 2.37-2.26 (m, 2H), 1.91-1.80 (m, 2H), 1.59-1.52 (m, 1H), 1.19 (s, 3H), 1.10-1.06 (m, 4H), 0.95 (s, 3H); MS (ES−) m/z 402.1, 404.1 (M−1).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([C:11]2[N:16]=[C:15]([NH:17][C:18]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=3)[CH:14]=[CH:13][CH:12]=2)=[CH:9][N:10]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:17][C:15]2[N:16]=[C:11]([C:8]3[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=3)[CH:12]=[CH:13][CH:14]=2)[CH:23]=1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(C4OCCO4)s3)n2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(C=O)s3)n2)c1
Temperature: 60 °C
Yield: 93.6 %

Procedure:
To a stirred solution of [6-(2-[1,3]dioxolan-2-yl-thiazol-5-yl)-pyridin-2-yl]-(4-methyl-pyridin-2-yl)-amine (270 mg, 0.793 mmol) in THF (8 mL) was added 2N HCl (2 mL). The mixture was heated at 60° C. overnight. After cooling, saturated NaHCO3 was added to basic pH then the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure to afford the title compound as a yellow solid (220 mg, 94%). 1H NMR (DMSO-d6, 300 MHz): δ=9.94 (s, 1H), 9.83 (s, 1H), 8.87 (s, 1H), 8.12 (d, J=4.9 Hz, 1H), 7.90 (s, 1H), 7.78 (m, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 6.80 (d, J=5.1 Hz, 1H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:36]=O>[Pd].C(O)CCC>[C:27]([C:25]1[CH:26]=[C:21]([CH2:20][CH2:19][N:18]([CH3:36])[CH2:17][CH2:16][C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:13])([CH3:15])[CH3:14])[CH:8]=2)[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]=1[OH:31])([CH3:30])([CH3:29])[CH3:28]
Reactant: C=O
Reactant: CC(C)(C)c1cc(CCNCCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCCCO
Product: CN(CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Yield: 100.9 %

Procedure:
Charge a suitable reaction vessel with 3.0 g (6.2 mmols) of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]amine, 2.2 g of 37% formaldehyde (27.1 mmols), 0.6 g of 10% Pd/C, and 15 mL of n-butanol. Purge with hydrogen and shake the vessel on a Parr Series 3900 Hydrogenation Apparatus at 60 psi (0.4 MPa) hydrogen pressure and room temperature for 5 hours. Dilute the resulting slurry with 30 mL of methylene chloride, filter, and concentrate the filtrate in vacuo to give 3.1 g of N,N-bis[β-(3,5-di-t-butyl-4-hydroxyphenyl)ethyl]methylamine as a yellow oil which slowly crystallizes on standing. GC area % analysis shows the product to be 98.8% pure.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1OCCOCCOCCOCCOCCOC1.C([O-])([O-])=O.[K+].[K+].[C:71](=[O:83])([O:79][CH:80](I)[CH3:81])[O:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][C:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:80]([O:79][C:71]([O:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:83])[CH3:81])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(I)OC(=O)OC1CCCCC1
Reactant: C/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(=O)OC2CCCCC2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a mixture of the product of Procedure 7 (35 g, 53.7 mmol) 18-crown-6 (4.0 g, 15 mmol) and well ground K2CO3 (9.45 g, 6.84 mmol) in dry DMF (330 ml) was added dropwise the cyclohexyl 1-iodoethyl carbonate (41 g, 138 mmol) at 0° C. under argon and the mixture was stirred for 1 hr. at 2°-4° C. The mixture was diluted with ethyl acetate (1.5 L) and washed well with water. The organic layer was separated, dried and evaporated under reduced pressure. The residue was chromatographed on a column of silica gel (400 g) and the column was eluted with n-hexane-dichloromethane (2:1 to 0:1). The fractions containing the desired product were combined and evaporated under reduced pressure to afford 27.3 g (62%) of the product as an amorphous powder.
Reaction SMILES: [BH4-].[Na+].O.O=C1CCC(=O)N1[O:11][C:12](=O)[CH2:13][CH:14]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1COCC1>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:13][CH2:12][OH:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)NC(CC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 24.5 %

Procedure:
A solution of NaBH4 (262 mg, 6.92 mmol) in 4:1 THF:H2O (20 ml) was cooled to 0° C. To this mixture was slowly added a solution of the ester from step (38a) (4.61 mmol) in THF (12 ml). Gas was evolved. When gas evolution ceased, the mixture was quenched by the careful addition of saturated aqueous ammonium chloride. The resulting solution was stirred at 0° C. for an additional 15 min. EtOAc (200 ml) was added and the resulting mixture was washed with saturated aqueous NaCl. The organic layer was dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (silica, 0-10% MeOH/CHCl3) gave 2-tert-butoxycarbonylamino-4-hydroxy-butyric acid benzyl ester (350 mg, 25% for 2 steps) as a clear, colorless oil: 1H NMR (300 MHz, Methanol-D) δ 7.23-7.43 (m, 5 H), 5.06-5.25 (m, 2 H), 4.00-4.57 (m, 2 H), 3.54-3.69 (m, 1 H), 1.67-2.12 (m, 2 H), 1.29-1.50 (m, 9 H). LC-MS (Method A, retention time: 1.25 min).
Reaction SMILES: [C:1]([C:5]([CH2:7][C:8]#[N:9])=O)([CH3:4])([CH3:3])[CH3:2].[NH2:10][NH2:11]>C(O)C>[CH3:2][C:1]([C:5]1[CH:7]=[C:8]([NH2:9])[NH:11][N:10]=1)([CH3:4])[CH3:3]
Reactant: NN
Reactant: CC(C)(C)C(=O)CC#N
Solvent: CCO
Product: CC(C)(C)c1cc(N)[nH]n1
Temperature: 25 °C

Procedure:
The ketone thus formed was dissolved in 150 ml of ethanol containing 32 g of hydrazine. The reaction mixture was heated at reflux for twelve hours, and then cooled to room temperature. Removal of the solvent by evaporation under reduced pressure provided a solid residue, which when triturated with 250 ml of petroleum ether, filtered and air dried, was identified as 12.5 g of 3-tert.-butyl-5-amino-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH:14]([CH3:18])[C:15](=O)[CH3:16]>C(#N)C>[NH2:1][C:2]1[C:3]2[N:4]([C:14]([CH3:18])=[C:15]([CH3:16])[N:12]=2)[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: COC(=O)c1cnc(N)c(N)c1
Reactant: CC(=O)C(C)Br
Solvent: CC#N
Product: COC(=O)c1cc(N)c2nc(C)c(C)n2c1
Yield: 59.1 %

Procedure:
Methyl 5,6-diaminonicotinate (0.9 g, 5.4 mmol) and 3-bromo-2-butanon (0.9 g, 6.0 mmol) were added to acetonitril (30 ml) and refluxed for 24 h. Upon cooling some of the product was filtered off as hydrobromide salt. 20 ml of the filtrate was evaporated under reduced pressure and diethyl ether was added. More product was filtrated off as hydrobromide salt. The salt was dissolved in methylene chloride and washed with a bicarbonate solution. The organic layer was separated, dried over Na2SO4 and evaporated under reduced pressure to give 0.7 g (59%) of the desired compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[F:11].[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19]>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.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[F:11])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(O)c1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: O=C(O)c1ccc(F)c(-c2ccc(F)c(F)c2)n1
Yield: 70 %

Procedure:
Method 1 was followed using 6-bromo-5-fluoropicolinic acid (1.0 equiv.) and 3,4-difluorophenylboronic acid (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.) to give 6-(3,4-difluorophenyl)-5-fluoropicolinic acid in 70% yield. LC/MS=254.1 (M+H), Rt=0.81 min.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:17]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C1COCC1.C(OCC)(=O)C.CO>[F:16][C:2]1([F:1])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:6][CH2:5][N:4]([CH3:17])[CH2:3]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCNCC(F)(F)C1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CN1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Temperature: 20 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
Combined tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate (49 mg, 0.207 mmol) and sodium cyanoborohydride (52 mg, 0.83 mmol) in THF (1.5 mL) and added 37% aqueous formaldehyde (0.077 mL, 1.037 mmol) and acetic acid (0.018 mL, 0.311 mmol) and then stirred at 20° C. for 16 h. Then methanol (300 uL) was added and the mixture was concentrated in vacuo to give a residue which was taken up in ethyl acetate (40 mL), washed with saturated aqueous sodium bicarbonate (50 mL) and brine, dried with magnesium sulfate and concentrated in vacuo to give the title compound (51 mg, 0.204 mmol, 98%) as a clear, colorless oil. MS: 251 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.46 (s, 9H) 2.50 (s, 3H) 2.73 (d, J=4.8 Hz, 2H) 2.92 (t, J=13.5 Hz, 2H) 3.55 (d, J=4.8 Hz, 2H) 3.75-3.94 (m, 2H).
Reaction SMILES: [Mg].Br[C:3]1[C:11]2[O:10][C:9]3[CH2:12][CH2:13][CH2:14][CH2:15][C:8]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:16](=[O:18])=[O:17].Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH2:15]1[C:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([C:16]([OH:18])=[O:17])[C:11]=3[O:10][C:9]=2[CH2:12][CH2:13][CH2:14]1
Reactant: O=C=O
Reactant: Brc1cccc2c3c(oc12)CCCC3
Agent: Cl
Agent: [Mg]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)c1cccc2c3c(oc12)CCCC3
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a suspension of magnesium (345 mg) in tetrahydrofuran (5 ml) was added 6-bromo-1,2,3,4-tetrahydrodibenzofuran (3.39 g) in tetrahydrofuran (15 ml) dropwise. The mixture was refluxed for 1 hour and cooled to 4° C. Dry ice (2.7 g) was added to the mixture and the mixture was stirred at ambient temperature for 30 minutes. To the mixture was added 3.6% hydrochloric acid and chloroform. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from n-hexane to give 1,2,3,4-tetrahydrodibenzofuran-6-carboxylic acid (2.60 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH:13]3[CH:24]4[CH:14]3[CH2:15][CH:16]3[N:21]([CH3:22])[C:20](=O)[CH2:19][O:18][CH:17]34)[N:10]([CH:25]([CH3:27])[CH3:26])[N:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].CO>O1CCCC1>[CH:25]([N:10]1[C:11]([CH:13]2[CH:24]3[CH:14]2[CH2:15][CH:16]2[N:21]([CH3:22])[CH2:20][CH2:19][O:18][CH:17]23)=[CH:12][C:8]([C:5]2[CH:4]=[C:3]([C:28]([F:30])([F:31])[F:29])[C:2]([NH2:1])=[N:7][CH:6]=2)=[N:9]1)([CH3:27])[CH3:26]
Reactant: CC(C)n1nc(-c2cnc(N)c(C(F)(F)F)c2)cc1C1C2CC3C(OCC(=O)N3C)C21
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)n1nc(-c2cnc(N)c(C(F)(F)F)c2)cc1C1C2CC3C(OCCN3C)C21
Temperature: 70 °C

Procedure:
To a stirred solution of (±)-6-(3-(6-amino-5-(trifluoromethyl)pyridin-3-yl)-1-isopropyl-1H-pyrazol-5-yl)-4-methylhexahydro-2H-cyclopropa[4,5]cyclopenta[1,2-b][1,4]oxazin-3(6bH)-one (0.040 g, 0.092 mmol) in tetrahydrofuran (5 mL) was added borane tetrahydrofuran complex (5 mL, 5 mmol). The reaction mixture was heated at 70° C. for 2 h under nitrogen. Methanol was added and the resulting solution was concentrated in vacuo. Purification by preparative HPLC afforded a 1.5:1 mixture of diastereomers (15 mg, 39%). LCMS (ESI): [MH]+=401.9 1H NMR (400 MHz, Methanol-d4) δ: 8.52 (d, J=3.6 Hz, 1 H), 8.32 (s, 1 H), 8.13 (s, 1 H), 6.31 (s, 0.6 H), 6.22 (s, 0.4 H), 4.85-4.82 (m, 1H), 4.06-4.02 (m, 1 H), 3.85-3.70 (m, 1.6 H), 3.50-3.45 (m, 0.4 H), 3.40-3.30 (m, 0.6 H), 3.20-3.17 (m, 0.4 H), 2.90-2.85 (m, 0.6 H), 2.79-2.65 (m, 3.4 H), 2.60 (s, 1 H), 2.37-2.36 (m, 1 H), 2.05-1.95 (m, 2 H), 1.90-1.80 (m, 1 H), 1.55-1.52 (m, 6 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:11]3[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](O)=[O:29])=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:31])[C:27]=1[C:28](=[O:29])[NH:16][C:13]1[CH:14]=[CH:15][N:10]2[N:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[N:17]=[C:11]2[CH:12]=1)=[O:22])[CH3:19]
Reactant: Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 57.8 %

Procedure:
The product was prepared in the same manner as described in example 28 using 2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (580 mg, 2.54 mmol) and 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (604 mg, 3.05 mmol) as starting materials. The reaction affords 5-[2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (600 mg, 57.8%) as white solid. mp.: 246-249° C., MS: m/z=409.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:23]([F:26])([F:25])[F:24])[C:3]=1[C:27](=[O:29])[NH2:28].CO[C:32](=O)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH3:41].[O-]CC.[Na+]>CCO>[CH3:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][C:32]1[NH:28][C:27](=[O:29])[C:3]2[C:4]([C:23]([F:26])([F:25])[F:24])=[N:5][N:6]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:14])[CH2:11][CH2:12]3)[C:2]=2[N:1]=1
Reactant: COC(=O)Cc1ccccc1OC
Reactant: NC(=O)c1c(C(F)(F)F)nn(C2CCN(C(=O)OCc3ccccc3)CC2)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Cc1nc2c(c(C(F)(F)F)nn2C2CCN(C(=O)OCc3ccccc3)CC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.8 %

Procedure:
To a stirred solution of 117 (327 mg, 0.795 mmol) in EtOH (3.2 mL) was added 2-Methoxyphenylacetic acid methyl ester (0.26 mL, 1.59 mmol), and then Sodium ethoxide (21% in EtOH, 0.6 mL, 1.59 mmol) and the resulting solution was allowed to stir for 1 h at room temperature, then for 3 h at 75° C. After the usual work-up the crude material was purified via Biotage (10% to 60% EtOAc/Hexane; 12M column) to afford 118 (98 mg, 22.8% yield) as white solid, LRMS (ESI): calc. 541.5; found 542.3 (MH)+.
Reaction SMILES: [CH2:1]([N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[CH:6][C:4]1=[O:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH2:1]([N:3]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([OH:14])=[C:6]([N+:15]([O-:17])=[O:16])[C:4]1=[O:5])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCn1c(=O)cc(O)c2ccccc21
Solvent: CC(=O)O
Product: CCn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21
Temperature: 100 °C

Procedure:
A suspension of 1-ethyl-4-hydroxy carbostyril (1.09 g; 0.00575 mole) in glacial acetic acid (5 ml) was swirled during the rapid addition of concentrated nitric acid (1.25 ml; d 1.42) and the dark liquid heated for 5 minutes at 100° C. The yellow solid which separated on cooling was filtered off and washed well with ethanol m.p. 154°-5° C (decomp). (Found; C, 56.54; H, 4.52; N, 11.56; C11H10N2O4 requires; C, 56.41; H, 4.30, N, 11.96%).
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[N:12]([CH3:25])[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[C:36]1([C:42]([O:44]C)=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>CC(O)(C)C>[C:1]([C:5]1[CH:28]=[CH:27][C:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:36]4([C:42]([OH:44])=[O:43])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:22][CH:23]=3)[N:12]([CH3:25])[C:11]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(Br)CCCCC1
Reactant: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCCc1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CN1C(=O)N(Cc2ccc(C(C)(C)C)cc2)CC1CCCc1ccc(OC2(C(=O)O)CCCCC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 1-(4-tert-butyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.074 g, 0.194 mmol) and potassium tert-butoxide (0.044 g, 0.392 nmol) in 2-methyl-2-propanol (8 mL) was heated to 60° C. under N2 and then and methyl 1-bromocyclohexanecarboxylate (0.274 g, 1.16 mmol) was added dropwise to the to 60° C. solution. Additional potassium tert-butoxide (0.044 g, 0.392 mmol) and methyl 1-bromocyclohexanecarboxylate (0.274 g, 1.16 mmol) was added to the reaction and it was stirred for 2 h. The reaction mixture was cooled and quenched with 1 N HCl. The mixture was then diluted with water and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.400 g of crude product that was purified by preparative HPLC to give 0.059 g (60%) 1-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-cyclohexanecarboxylic acid. 1H NMR. HRMS (ES+) m/z exact mass calcd for C31H43N2O4 [M+1] 507.3223, found 507.3237.