Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[OH-].[Na+].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11](Cl)=[O:12])([O-:8])=[O:7]>O1CCOCC1>[CH3:1][N:2]([CH3:3])[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: CNC
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccccc1[N+](=O)[O-]
Yield: 57.2 %

Procedure:
A mixture of dimethylamine (30 g, 270 mmol) and sodium hydroxide (7.2 g, 180 mmol) in 60 mL of dioxane was stirred and 2-nitrobenzoyl chloride (23.8 mL, 180 mmol) in 100 mL of dioxane was added dropwise. The mixture was stirred at room temperature for approximately 12 hours and then partitioned between 100 mL of saturated sodium bicarbonate solution and 150 mL of ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×100 mL) and the combined ethyl acetate was washed with brine, dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 4% methanol/methylene chloride to give N,N-dimethyl-2-nitrobenzamide (20 g, 103 mmol), m.p. 74°-76° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:44])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][C:24]=3[NH:34][C:35]([C:37]3[CH:41]=[C:40]([CH3:42])[N:39]([CH3:43])[N:38]=3)=O)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>[OH-].[Na+].C(O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:44])[O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[C:23]4[CH:28]=[C:27]([Cl:29])[C:26]([C:30]([F:32])([F:31])[F:33])=[CH:25][C:24]=4[N:34]=[C:35]3[C:37]3[CH:41]=[C:40]([CH3:42])[N:39]([CH3:43])[N:38]=3)=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(Nc3cc(Cl)c(C(F)(F)F)cc3NC(=O)c3cc(C)n(C)n3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NC(=O)OCCc2ccc(-n3c(-c4cc(C)n(C)n4)nc4cc(C(F)(F)F)c(Cl)cc43)cc2)cc1
Temperature: 50 °C
Reaction time: 85 h
Yield: 21.3 %

Procedure:
A mixture of 2-(4-{[5-chloro-2-{[(1,5-dimethyl-1H-pyrazol-3-yl)carbonyl]amino}-4-(trifluoromethyl)phenyl]amino}phenyl)ethyl (4-methylphenyl)sulfonylcarbamate (step 3, 145 mg, 0.223 mmol) in 2N NaOH (1 ml) and ethanol (2 ml) was stirred at 50° C. for 85 h. After cooling, the pH value was adjusted to 4.0 by addition of 2N HCl. The mixture was diluted with water (80 ml), and extracted with dichloromethane (80 ml×3). The combined organic layer was washed with brine (50 ml), dried (MgSO4), and concentrated. Purification by PTLC eluting with hexane/ethyl acetate (1:3) to afford 30 mg (21%) of the title compound as a red solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:22][C:23]([N:25]([CH3:27])[CH3:26])=[O:24]>CN(C=O)C.O>[CH3:26][N:25]([CH3:27])[C:23](=[O:24])[CH2:22][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Yield: 113.6 %

Procedure:
A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), and 2-chloro-N,N-dimethylacetamide (0.47 mL, 4.5 mmol) in DMF (14 mL) was heated in a microwave at 90° C. for 1 hr. The crude reaction mixtures were then diluted with water (300 mL) and extracted with ethyl acetate (3×50 mL). Product was purified by silica gel column using DCM/EtOAc/MeOH (8/1.5/0.5) as eluent to provide N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide (1.3 g) as a light yellow oil. ESI-MS:m/z 280.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([NH:14][CH2:15][C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)([CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([N:14]([CH2:15][C:16]2[C:17](=[O:27])[N:18]([CH3:26])[C:19]3[C:24]([CH:25]=2)=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:43]([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:44])([CH3:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Cn1c(=O)c(CNC2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1c(=O)c(CN(C(=O)C2CCCCC2)C2(C)CCN(Cc3ccccc3)C2)cc2ccccc21
Reaction time: 2 h

Procedure:
To 3-{[(1-benzyl-3-methylpyrrolidin-3-yl)amino]methyl}-1-methylquinolin-2(1H)-one (1846 mg, 5.11 mmol) in CH2Cl2 (25 ml) was added DIEA (1.338 ml, 7.66 mmol). Cyclohexane carbonyl chloride (0.757 ml, 5.62 mmol) was added and the reaction stirred for 2 hours. The reaction was quenched with MeOH then concentrated in vacuo. The resulting material was twice purified by silica gel chromatography on an Isco Companion (5-35% acetone/hexane for first run, 5-25% acetone/hexane for second run). 2.12 g, 88% over two steps.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[N:10][N:11]([CH2:17][C:18]([OH:20])=O)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:33]1C=CN=C1)=O.[OH-].[NH4+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)=[N:10][N:11]([CH2:17][C:18]([NH2:33])=[O:20])[C:12]=2[C:13]([F:14])([F:16])[F:15])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2nn(CC(=O)O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nn(CC(N)=O)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.9 %

Procedure:
To a solution of [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (Example 10) (0.24 g, 0.54 mmol) in THF (6 mL) was added 0.10 g of 1,1'-carbonyldiimidazole at 25° C. under nitrogen. After gas evolution had ceased (approx. 30 minutes), 6 mL conc. ammonium hydroxide was added and the mixture stirred at 25° C. for 18 hours. The reaction mixture was diluted with water, extracted with two portions ethyl acetate and the organic layer washed successively with dilute aqueous HCl and brine, dried over MgSO4 and concentrated in vacuo. Recrystallization from chloroform/acetone gave [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide as a white crystalline solid (0.15 g, 34%). Elemental analysis for C19H15N3F4SO3Calc'd: C, 51.70, H, 3.42, N, 9.52. Found: C, 51.46, H, 3.35, N, 9.39.
Reaction SMILES: [Cl:1][C:2]12[C:10]([O:13][CH3:14])([O:11][CH3:12])[C:5]([Cl:15])([C:6]([Cl:9])=[C:7]1[Cl:8])[CH:4](O)[CH:3]2O.I([O-])(=O)(=O)=O.[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[Cl:15][C:5]12[C:10]([O:11][CH3:12])([O:13][CH3:14])[C:2]([Cl:1])([C:7]([Cl:8])=[C:6]1[Cl:9])[CH2:3][N:31]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[CH2:4]2
Reactant: COc1ccc(CN)cc1
Reactant: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C(O)C2O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(CN2CC3(Cl)C(Cl)=C(Cl)C(Cl)(C2)C3(OC)OC)cc1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
1,4,5,6-Tetrachloro-7,7-dimethoxy-bicyclo[2.2.1]hept-5-ene-2,3-diol (1.23 g, 3.80 mmol) and sodium periodate (1.19 g, 3.80 mmol) were stirred vigorously for 1.5 h in DCE (10 mL) and water (10 mL). The di-aldehyde was extracted with DCE (2×15 mL), washed with water (5×10 mL, or until no reaction to starch iodide is observed in the aqueous wash), then filtered through a cotton plug under N2 into a slurry of p-methoxybenzylamine (0.52 mL, 3.99 mmol) and NaBH(OAc)3 (2.58 g, 12.16 mmol) in DCE (10 mL). After 3 h at room temperature the reaction was judged complete by TLC. The solvent was removed in vacuo, and the residue was quenched with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×30 mL), washed with saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4, filtered through a silica pad (2×3 in), eluted with 100% EtOAc and concentrated to yield the title compound as a white solid (1.32 g, 82%). (TLC 30% EtOAc/hexanes Rf 0.65); 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 3.77 (s, 3H), 3.61 (s, 2H), 3.59 (s, 3H), 3.56 (s, 3H), 2.76 (d, J=11.4 Hz, 2H), 2.71 (d, J=11.1 Hz, 2H); GCMS m/z 427 (M)+.
Reaction SMILES: [NH2:1][C:2]1[N:29]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH2:25]Cl)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:35])[C:3]=1[C:36]([NH2:38])=[O:37].[C:39]([O-])([O-])=[O:40].[K+].[K+]>CO>[NH2:1][C:2]1[N:29]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:6]2[N:7]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:40][CH3:39])[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:27][CH3:28])[N:9]=[CH:10][C:5]=2[C:4](=[O:35])[C:3]=1[C:36]([NH2:38])=[O:37]
Reactant: COc1cc(C2CCN(CCCl)CC2)ccc1Nc1ncc2c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCCN1CCC(c2ccc(Nc3ncc4c(=O)c(C(N)=O)c(N)n(CC(C)(C)O)c4n3)c(OC)c2)CC1
Yield: 75.5 %

Procedure:
To a suspension of 0.29 g (0.54 mmol) of the product prepared in step 22.1 in 9 mL of anhydrous methanol is added 0.37 g (2.68 mmol) of K2CO3, and the mixture is refluxed for 1 hour. It is evaporated to dryness and the residue is taken up in water and CH2Cl2. The organic phase is dried over MgSO4, filtered and concentrated under vacuum. The crude product is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (90/10). After triturating in methanol, 0.22 g of the expected product is finally obtained in the form of a yellow solid. Yield=78%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([N+:19]([O-:21])=[O:20])=[C:11]([CH:10]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: O=[N+]([O-])O
Product: COc1cc([N+](=O)[O-])c(C=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To concentrated nitric acid (200 ml.) maintained at 0° C. is added 3-benzyloxy-4-methoxybenzaldehyde (48 g., 0.198 mole) over a 30 minute period with stirring. When addition is complete, the temperature is allowed to rise to 15° C. and stirring continued for another 30 minutes. The mixture is then added to ice-water and the yellow precipitate collected by filtration and dried. Yield = 52.8g. (94%); m.p. 131°-132° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][NH:10][C:9](=O)[N:8]=2)=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.CN(C)C=O>>[Cl:16][C:9]1[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1nc(-c2ccncc2)cc[nH]1
Solvent: CN(C)C=O
Product: Clc1nccc(-c2ccncc2)n1

Procedure:
With ice-bath cooling under argon, 4-(4-pyridyl)-2(1H)-pyrimidinone (13.45 g, 77.7 mmol) and thionyl chloride (92 ml) were combined. N,N-Dimethylformamide (13.2 ml, 170.5 mmol) was added slowly and the mixture was heated to reflux for 1 h. It was evaporated and co-distilled with toluene. At 0° C., water was added to the remainder, then 10% ammonium hydroxide until neutral followed by extraction with dichloromethane. Drying of the organic solution was followed by evaporation and the resultant solid was recrystallized from acetone. MS (m/z): 192.1,194.0 (M+H)+; C9H6ClN3 requir. 191.6.
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)O[CH2:2]1.C([O:14][C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=1)C>>[CH2:1]([O:11][C:4]1[CH:5]=[CH:6][C:7]([CH:18]2[CH2:19][CH2:20][C:15](=[O:14])[CH2:16][CH2:17]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(Br)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Product: CCOc1ccc(C2CCC(=O)CC2)cc1

Procedure:
Cyclohexane-1,4-dione monoethyleneacetal is reacted with a Grignard reagent prepared from 1-ethoxy-4-bromobenzene, and the product is dehydrated and then hydrogenated in the same manner as in process A (if desired, ethyleneacetal is re-introduced). The acetal moiety is removed to obtain 4-(4-ethoxyphenyl)cyclohexanone, which is then deuterated in the same manner as in process A to obtain 4-(4-ethoxyphenyl)cyclohexanone-2,2,6,6-d4. The deuterated compound is reacted with a Grignard reagent prepared from propyl bromide, and the product is dehydrated and hydrogenated. The cis-compound is separated to obtain 1-(trans-4-propylcyclohexyl-3,3,5-d3)-4-ethoxybenzene. ##STR61##
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:5])[CH3:2].[CH2:17]([OH:27])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][O:27][C:7]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[O:11])=[O:16]
Reactant: OCCCCCCCCCO
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Product: CCOC(=O)NC(=O)c1ccccc1C(=O)OCCCCCCCCCO

Procedure:
According to the same manner as described in Example 1 except for reacting N-ethoxycarbonylphthalimide with 1,9-nonanediol under conditions shown in Table 19, ethyl N-{2-(9-hydroxynonyloxycarbonyl)benzoyl)carbamate was obtained. Characteristics and identified structure of the resulting compound are shown in Table 8.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[N:8]=[CH:7][C:6]([C:9](=[N:11][OH:12])[NH2:10])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21](Cl)=O>>[Cl:15][C:16]1[CH:20]=[CH:19][S:18][C:17]=1[C:21]1[O:12][N:11]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:13])([F:1])[F:14])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NC(=NO)c1ccc(C(F)(F)F)nc1
Product: FC(F)(F)c1ccc(-c2noc(-c3sccc3Cl)n2)cn1

Procedure:
The title compound was prepared from 6-trifluoromethyl-pyridine-3-amidoxime (418 mg, 2.04 mmol) and 3-chloro-thiophene-2-carbonyl chloride (369 mg, 2.04 mmol) similar to Example 16, and yielded 538 mg (80%) of white solid. 1H NMR (CDCl3): 9.49 (m, 1H), 8.63 (m, 1H), 7.85 (dd, J=8.24, 0.82 Hz, 1H), 7.66 (d, J=5.49 Hz, 1H), 7.17 (d, J=5.22 Hz, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:8]=2[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19][C:20](=[O:24])[CH2:21][CH:22]=[CH2:23])([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:9][C:8]1[CH:10]=[C:11](/[CH:23]=[CH:22]/[CH2:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:24])[CH:12]=[CH:13][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(Br)cc1-c1ccccc1
Reactant: C=CCC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C/C=C/c1ccc(-c2ccccc2)c(N)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
2-Phenyl-4-bromoaniline (564.7 mg, 2.28 mmol) was dissolved in N,N-dimethylformamide (25 mL) and, at room temperature, thereto were added tert-butyl-3-butenoate (582.5 mg, 4.10 mmol), tri-(o-tolyl)phosphine (1.87 g, 6.16 mmol), and diisopropylethylamine (0.78 mL, 4.56 mmol). The reaction mixture was deaerated, palladium acetate (67.4 mg, 0.30 mmol) was added, and the mixture was deaerated again. After stirring at 90° C. overnight, the reaction mixture was filtered through celite and washed with ethyl acetate (120 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (50 mL), thereafter dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by a silica gel column to obtain tert-butyl (3E)-4-(3-amino-4-phenylphenyl)-3-butenoate (555.8 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>>[Cl:9][C:10]1[CH:15]=[C:14]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)nc1
Product: Nc1ccc(Oc2ccnc(Cl)c2)nc1
Yield: 34.8 %

Procedure:
Using a procedure analogous to Example A1, 5-amino-2-hydroxypyridine (10.15 g, 92 mmol) and 2,4-dichloropyridine (13.64 g, 92 mmol) were combined to provide 6-(2-chloropyridin-4-yloxy)pyridin-3-amine (7.09 g, 35% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.12 (m, 1H), 7.61 (m, 1H), 7.26 (m, 1H), 7.0 (s, 1H), 6.97-6.94 (m, 2H), 5.4 (brs, 2H); MS (ESI) m/z: 222.0 (M+H+).
Reaction SMILES: O[C:2]1([C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:24][C:21]([F:22])([F:23])[C:19]1[CH:18]=[CH:17][N:16]=[C:15]([C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:4][CH:3]=2)[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(F)(F)F)ccn2)CC1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccn2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 53.3 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[4-(trifluoromethyl)pyridin-2-yl]piperidine-1-carboxylate (2.00 g, 2.31 mmol) in pyridine (15.9 mL) cooled in an ice bath was slowly added thionyl chloride (0.84 mL, 12 mmol). The mixture was allowed to warm to room temperature and stirred overnight (17 h). The brown reaction mixture was quenched with ice water and extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0-10% B over 25 min. Bottle A=hexanes, Bottle B=EtOAc) to give 404 mg (53%) of desired product as light brown oil. LC-MS calculated for C16H19F3N2O2: (M+H) 329; found 273.1 (M-tBu+1).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>>[CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:25][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Product: CCCCCCCCOc1ccc(CNCc2ccc(C(F)(F)F)cc2)cc1
Yield: 86 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 4-(octyloxy)benzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (86%). 1H NMR (CDCl3, 300 MHz) δ 7.57 (d, 2H, J=7.9 Hz), 7.45 (d, 2H, J=7.9 Hz), 7.22 (m, 2H), 6.85 (m, 2H), 3.93 (t, 2H, J=6.5 Hz), 3.84 (s, 2H), 3.72 (s, 2H), 1.82-1.70 (m, 2H), 1.50-1.23 (m, 10H), 0.89 (m, 3H). M−(LC/MS(ESI)): 406.3 HPLC (Condition A), Rt: 4.42 min (HPLC purity: 98.7%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:18][O-].[Na+].C(O)(=O)C>O>[Cl:18][C:7]1[C:6]([OH:9])=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:10])[F:11])[N:8]=1
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: [O-]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1ccc(C(F)(F)F)nc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 188.8 %

Procedure:
A solution of 6-(trifluoromethyl)pyridine-3-ol (7 g, 40 mmol) and sodium carbonate (4.5 g, 4.2 mmol) in water (200 mL) was cooled in an ice bath. 0.7N Sodium hypochlorite solution (63.9 mL, 4.29 mmol) was added portionwise over 30 minutes, and the reaction stirred at 0° C. for 2 hours. The reaction mixture was acidified using acetic acid, and extracted into EtOAc (3×50 mL). The combined organics were washed with brine (2×50 mL), dried (MgSO4), filtered and concentrated. The product was purified by flash chromatography (0 to 25% EtOAc in hexanes) giving the title compound (1.6 g, 20%) as a solid. 1H NMR (400 MHz; CDCl3) δ 7.61 (1H, d), 7.45 (1H, d), 5.83 (1H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](O)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19].C(Cl)(=O)C([Cl:23])=O.CN(C)C=O>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:23])=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:18][CH3:19]
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCCCl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCl
Yield: 70.4 %

Procedure:
A solution of 8 g (28.7 mmol) of 7-(2-Chloro-ethoxy)-4-hydroxy-6-methoxy-quinoline-3-carbonitrile and 18.2 g (143.5 mmol) of oxalyl chloride in 80 ml of methylene chloride containing 0.26 g of dimethylformamide was stirred at reflux for 2.5 hr. The solvent was removed. The residue was mixed with cold dilute sodium hydroxide and extracted several time with ethyl acetate and tetrahydrofuran. The combined extracts were dried over magnesium sulfate and the solution was passed through a short silica gel column. The solvents were removed giving 6.0 g of the title compound as an off-white solid that is used without additional purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH3:15]I>C(O)C>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([S:10][CH3:15])[NH:9][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: CI
Solvent: CCO
Product: CSc1nc2ccc(C(F)(F)F)cc2[nH]1
Yield: 81.9 %

Procedure:
A suspension of 20.0 g (0.092 mole) of 5-trifluoromethyl-2-mercaptobenzimidazole and 13.1 g (0.092 mole) of methyl iodide in 200 ml of ethanol is heated to the boil for three hours. The solvent is stripped off in vacuo and the residue is recrystallized from acetonitrile. 17.5 g (82%) of 5-trifluoromethyl-2-methylthio-benzimidazole of m.p. 145°-146° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[O:17][C:7]1([CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:21].[Br-].[CH2:23]1COC[CH2:24]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[O:17][C:7]1([CH2:12][CH2:11][CH:10]([C:13]([CH3:16])([CH3:14])[CH3:15])[CH2:9][CH2:8]1)[CH2:6][C:5]2([CH:23]=[CH2:24])[OH:21]
Reactant: C1CCOC1
Reactant: CC(C)(C)C1CCC2(CC1)CC(=O)c1cc(Br)ccc1O2
Agent: [Br-]
Product: C=CC1(O)CC2(CCC(C(C)(C)C)CC2)Oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 6-bromo-4′-t-butylspiro[chroman-2,1′-cyclohexan]-4-one (2.155 g, 6.13 mmol) in anhydrous THF (20 mL) at −78° C. is added a solution of vinylmagnesiun bromide in THF (1 M, 9.2 mL, 9.2 mmol) dropwise within 30 min. The reaction temperature is allowed to warm to rt and stirred for another 2 h. The reaction is chilled to 0° C. and quenched with sat. aq. NH4Cl, and extracted with ethyl acetate (2×40 mL). The combined organic phases are washed with H2O and brine, then dried over Na2SO4, and filtered. The filtrate is concentrated and the residue is purified through flash chromatography on silica gel to afford 6-bromo-4′-tert-butyl-4-vinylspiro[chroman-2,1′-cyclohexan]-4-ol as an oil (1.907 g, 82%). MS ESI +ve m/z 361 (M+H—H2O)+.