Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:20])[C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:15]=2)=[CH:7][CH:6]=1.[CH2:22]([NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:41]=[C:37]([C:38]([NH2:40])=[O:39])[C:36]([OH:42])=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[CH2:22]([N:29]([CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([C:38](=[O:39])[NH2:40])[CH:41]=1)[CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:20])[C:13]([C:16]([F:17])([F:19])[F:18])=[CH:14][N:15]=2)=[CH:9][CH:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1c(C(F)(F)F)cnc1-c1ccc(OCC2CO2)cc1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Solvent: CC(C)O
Product: Cn1c(C(F)(F)F)cnc1-c1ccc(OCC(O)CN(CCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1

Procedure:
A solution of 5 g of the resulting 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-5-(trifluoromethyl)-1H-imidazole and 4.7 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 100 ml of isopropanol is heated under reflux for 15 hours and the solvent is subsequently removed in a rotary evaporator. The crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[1-methyl-5-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]-2-propanol obtained in the form of an oil is further processed in that form.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18](O)=[O:19])[CH:9]=2)=[CH:5][CH:4]=1.[Cl:23]CCl.S(Cl)(Cl)=O>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[C:16]3[O:15][CH:14]=[CH:13][C:12]=3[CH:11]=[C:10]([CH2:17][C:18]([Cl:23])=[O:19])[CH:9]=2)=[CH:5][CH:4]=1
Reactant: ClCCl
Reactant: CSc1ccc(Cc2cc(CC(=O)O)cc3ccoc23)cc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CSc1ccc(Cc2cc(CC(=O)Cl)cc3ccoc23)cc1

Procedure:
A solution of 7-(4-methylthiobenzyl)benzofuran-5-ylacetic acid (10 g), dichloromethane (100 ml), thionyl chloride (10.0 ml) and dimethylformamide (0.2 ml) was stirred at room temperature for 6 hours. The solvent was then evaporated to give a residue which contained the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][C:6]1([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]1.[CH3:15][C:16]1[C:20]([CH:21]([OH:31])[CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:19]([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[O:18][N:17]=1>>[OH:31][CH:21]([C:20]1[C:16]([CH3:15])=[N:17][O:18][C:19]=1[C:32]1[CH:33]=[CH:34][C:35]([C:2]2[CH:14]=[CH:13][CH:12]=[C:4]([CH2:5][C:6]3([C:9]([OH:11])=[O:10])[CH2:8][CH2:7]3)[CH:3]=2)=[CH:36][CH:37]=1)[CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)C1(Cc2cccc(Br)c2)CC1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1C(O)CCCc1ccccc1
Product: Cc1noc(-c2ccc(-c3cccc(CC4(C(=O)O)CC4)c3)cc2)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-(3-bromo-benzyl)-cyclopropanecarboxylic acid and 1-{3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]isoxazol-4-yl}-4-phenyl-butan-1-ol.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:31]Br.O>C(O)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([Br:31])[C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CN(C)C(=O)Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C(=O)C(Br)c1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-N,N-dimethylacetamide (1.1 g, 1 eq.) and sodium acetate (761 mg, 3 eq.) in acetic acid (15 ml), was added bromine (158 ul, 1 eq.) and the reaction was stirred at room temperature for 4 h. Water was added and the product extracted into ethyl acetate. The ethyl acetate layer was washed several times with water, saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated to give 2-(3-benzyl-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-2-bromo-N,N-dimethylacetamide (1.44 g) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][C@H:33]([CH3:36])[CH2:34][OH:35]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][C@H:33]([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: C[C@@H](N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Product: C[C@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2R)-2-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, d, J=8 Hz), 8.50 (1H, s), 7.77 (1H, s), 7.32 (2H, dd, J=8.6, 6 Hz), 7.12 (2H, t, J=8.6 Hz), 5.12 (2H, m), 5.00 (1H, br), 4.11 (2H, s), 4.03 (1H, m), 3.44 (2H, m), 3.12 (3H, s), 2.82 (3H, s), 1.15 (3H, d, J=7 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1881.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17].[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3]1[C:8]([CH2:9][Br:18])=[CH:7][CH:6]=[CH:5][C:4]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[F:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1c(C)cccc1Oc1ccccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1c(CBr)cccc1Oc1ccccc1F
Yield: 114.2 %

Procedure:
A mixture of 2-fluorophenyl 2-methoxy-3-methylphenyl ether (11.5 g), N-bromosuccinimide (9 g) and azobisisobutyronitrile (0.9 g) in benzene (100 ml) was treated in a similar manner to that of Example 5-(3) to give oily 2-fluorophenyl 2-methoxy-3-bromomethylphenyl ether (17.6 g).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH2:17])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1.CCN(CC)CC.Cl[C:27]([O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:28]>C1COCC1>[Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:16][CH2:15][C@@H:14]([NH:17][C:27](=[O:28])[O:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:18])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)COC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](N)C3)nc(Cl)nc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c(N3CC[C@@H](NC(=O)OCC(C)(C)C)C3)nc(Cl)nc2c1
Reaction time: 0.08 h
Yield: 69.8 %

Procedure:
A solution of (R)-1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-amine (100 mg, 0.38 mmol) in 2 mL of THF was cooled to −30° C. To it was added Et3N followed by the addition of neopentyl chloroformate (53 μL, 0.38 mmol) dropwise. The reaction was complete after 5 minutes. The reaction was quenched with water, the layers separated, and the aqueous layer was twice extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification via silica gel chromatography using 0%-10% EtOAc in DCM gave (R)-neopentyl 1-(2-chloro-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (100 mg, 70% yield). LC/MS: m/z 377.5 (M+H)+ at 2.90 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([O:3][C:4](=[O:27])[C@@H:5]([O:25][CH3:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.Br[CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][O:24][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:25][CH3:26])[C:4]([OH:3])=[O:27])=[CH:12][CH:11]=3)=[CH:23][CH:22]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: BrCC1CCCCC1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(O)cc2)cc1)OC
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OCC3CCCCC3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-{4-[3-(4-hydroxy-phenoxy)-propoxy]-phenyl}-2-methoxy-propionic acid ethyl ester (Example 263, Step B) and (bromomethyl)cyclohexane following the procedure described for Example 264.
Reaction SMILES: [C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([OH:17])=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([NH:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]12([C:11](=[O:21])[CH2:12][N:13]3[CH2:20][CH2:19][CH2:18][C@H:14]3[C:15]([N:29]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:30](=[O:40])[C@H:31]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[NH2:32])=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: N[C@@H](Cc1ccccc1)C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N[C@@H](Cc1ccccc1)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 22 °C
Yield: 80.3 %

Procedure:
Using the procedure described previously, a solution of 1-(2-adamantan-1-yl-2-oxoethyl) L-proline (100 mg, 0.34 mmol, 1.0 eq), L-phenylalanine N-benzylamide (175 mg, 686 umol, 2.0 eq) and dichloromethane (1.0 mL), was cooled to 0° C., and treated with triethylamine (286 uL, 2.0 mmol, 6.0 eq). To this chilled solution was added a 50% solution of 1-n-propylphosphonic acid cyclic anhydride in dichloromethane (436 uL, 0.68 mL, 2.0 eq). When TLC indicated the reaction was complete, the solution was allowed to warm to 22° C., washed with satd aq NaHCO3, concentrated in vacuo, and purified by flash chromatography to provide 144 mg (80%) of L-phenylalanine, N-[1-(2-adamantan-1-yl-2-oxoethyl)-L-prolyl] benzylamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[Br:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Reactant: Brc1cccc(N2CCNCC2)c1
Product: COc1nc2cc(C)c(C)cc2nc1NC(=O)N1CCN(c2cccc(Br)c2)CC1
Yield: 69 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3-bromo phenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 69%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 3H), 2.40 (s, 3H), 3.22-3.31 (m, 4H), 3.73-3.76 (m, 3H), 4.13 (s, 4H), 6.85 (m, 1H), 7.00-7.20 (m, 3H), 7.40 (br s, 1H), 7.53 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:15]([CH2:19][CH2:20][NH2:21])[N+:16]([O-:18])=[O:17].C(OC(C)C)(C)C>>[O:15]([CH2:19][CH2:20][NH:21][C:8](=[S:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[N+:16]([O-:18])=[O:17]
Reactant: NCCO[N+](=O)[O-]
Reactant: OC(=S)Cc1ccccc1
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])OCCNC(=S)Cc1ccccc1
Yield: 66.9 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.72 g of phenylthioacetic acid and 0.60 g of 2-nitroxyethylamine nitrate, 0.57 g of the title compound was obtained as colorless powdery crystals (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[C:7]([N+:22]([O-])=O)[CH:6]=1)(=[O:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:12])=[O:13])=[C:7]([NH2:22])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2)c(N)c1
Reaction time: 7 h
Yield: 106.8 %

Procedure:
To a solution of 4-acetylamino-2-nitro-N-(4-chlorophenyl)benzenesulfonamide (4.85 g) in ethyl acetate (485 ml) was added 10% palladium on carbon, and the mixture was hydrogenated at room temperature under atmospheric pressure for seven hours. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was triturated with diisopropyl ether and collected by filtration to give 4-acetylamino-2-amino-N-(4-chlorophenyl)benzenesulfonamide as colorless powder (4.76 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[CH:25]([CH3:27])[CH3:26])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1ccccc1O
Product: CC(C)c1ccccc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 92.9 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted with 2-isopropyl phenol (18 mg, 0.12 mmol) to give the title compound (49 mg, 97%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1.Cl.O>CO.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[C@H:13]1[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)[N:7]=[C:6]2[C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1
Reactant: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8.5 g of (+/-)-cis-8,9-dimethoxy-6-(4-nitrophenyl)-1,2,3,4,4a,10b-hexahydrophenanthridine are dissolved in 200 ml of methanol, and the solution is treated with 5 ml of concentrated hydrochloric acid, 20 ml of water and 800 mg of iron powder and stirred overnight at RT. The reaction mixture is filtered, the filtrate is concentrated, the residue is extracted with sodium hydrogencarbonate solution/ethyl acetate, and the organic phase is dried using sodium sulfate and concentrated. The residue is chromatographed on silica gel using a mixture of toluene/dioxane/triethylamine in the ratio 40:20:2. After concentration of the corresponding eluate fractions, 5.5 g (70.5% of theory) of the title compound of m.p. 159.5-161° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OC/C=C\CCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OC/C=C\CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 65.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (1.8 g, 13 mmol) and (Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.43 g, 9.7 mmol) in acetonitrile (100 ml) was heated at reflux for 11/2 hours. At the end of the reaction, the solvent was removed and the inorganics were filtered after addition of dichloromethane (250 ml). The dichloromethane solvent was removed again. The crude oil was purified on two flash chromatography columns to give a colorless oil (2.78 g). The oil was solidified by vigorously drying on a vacuum pump. Recrystallization from ethanol (10 ml) and hexane (2 ml) gave analytically pure (Z)-1-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy-3-methoxy-phenyl]ethanone, 1.83 g,m.p.=57-59° C.
Reaction SMILES: Cl.[CH:2]1([NH:7][C:8]([NH2:10])=[NH:9])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[N:23]2[N:24]=[C:25]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[C:26]([C:27](=O)[C:28]#[CH:29])=[C:22]2[CH:21]=[CH:20][CH:19]=1>C(O)C>[Cl:17][C:18]1[N:23]2[N:24]=[C:25]([C:31]3[O:32][CH:33]=[CH:34][CH:35]=3)[C:26]([C:27]3[CH:28]=[CH:29][N:10]=[C:8]([NH:7][CH:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)[N:9]=3)=[C:22]2[CH:21]=[CH:20][CH:19]=1
Reactant: C#CC(=O)c1c(-c2ccco2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopentylguanidine hydrochloride (1.53 g, 9.38 mmol) and potassium carbonate (0.78 g. 5.63 mmol) were added to 80 mL of ethanol. The suspension was stirred at room temperature for 1 hour. 1-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.27 g, 4.69 mmol) was added to the resultant solution and stirred at room temperature for 24 hours. The reaction mixture was concentrated and ethyl acetate and water were added. The phases were separated, the organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography (3:7 ethyl acetatehexanes). gave 4-[7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (520 mg, 30%) as a yellow solid. 1H NMR (CDCl3): δ 8.28 (d, 1H), 8.22 (d, 1H), 7.58 (d, 1H), 7.23 (m, 1H), 7.04 (d, 1H), 6.92 (d, 1H), 6.62 (d, 1H), 6.53 (m, 1H), 5.16 (d, 1H), 4.35 (m, 1H), 2.07 (m, 2H), 1.77–1.52 (m, 6H). MS m/z 380 (M+1).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][CH:4]=[C:3]([CH:9]=[O:10])[CH:2]=1.[CH2:11]([Mg]Cl)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>O1CCCC1>[OH:8][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([CH:9]=[O:10])=[CH:2][CH:1]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC[Mg]Cl
Reactant: O=Cc1ccc(C=O)cc1
Solvent: C1CCOC1
Product: CCCCCCCCC(O)c1ccc(C=O)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.2 %

Procedure:
Terephthaldicarboxaldehyde (2.00 g, 14.91 mmol) was dissolved in tetrahydrofuran (25 ml) and cooled to 0° C. Octylmagnesium chloride (7.5 ml, 2.0M in THF, 15 mmol) was added dropwise. After 15 minutes, the reaction was quenched with 2N aqueous hydrochloric acid (50 ml) and diluted with ethyl acetate (50 ml). The organic layer was separated, washed with sat'd NaCl (50 ml), dried over magnesium sulfate and concentrated. Silica gel chromatography eluting with 91:9 v/v hexane/EtOAc gave 0.19 g (0.77 mmol, 5.1%) of the title compound: 1H NMR (500 MHz) δ 10.0 (s, 1H), 7.87 (d, J=8.0, 2H), 7.52 (d, J=8.3, 2H), 4.75-4.80 (m, 1H), 1.68-1.82 (m, 2H), 1.22-1.45 (m, 12H), 0.91 (t, J=7.0, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20](=[O:28])[CH2:21]P(OC)(OC)=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl-].[Li+].[F:40][C:41]([F:55])([F:54])[C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH:45]=O>C(#N)C>[F:40][C:41]([F:54])([F:55])[C:42]1[CH:43]=[C:44]([CH:45]=[CH:21][C:20](=[O:28])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:47]=[C:48]([C:50]([F:51])([F:52])[F:53])[CH:49]=1
Reactant: COP(=O)(CC(=O)C(Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)OC
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h

Procedure:
A solution of the product of part (b) (69.0 g) in acetonitrile (600 ml) was stirred with diisopropylethylamine (43.3 g), and anhydrous lithium chloride (14.13 g) for 30 minutes before adding 3,5-bistrifluoromethylbenzaldehyde (55 g) in acetonitrile (200 ml). The reaction was stirred for two hours then the solvent was removed and the residue partitioned between ethyl acetate and water. The organic phase was washed with 10% citric acid (500 ml), water (500 ml), saturated sodium bicarbonate (500 ml) and water (500 ml). The solution was dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica using ethyl acetate/petroleum ether (1:4) to yield the title compound as a pale yellow solid, mp=137°-138° C.; found: C, 59.23; H, 4.79; N, 5.35; C26H24F6N2O3 requires C, 59.32; H, 4.60; N 5.32%.
Reaction SMILES: [OH:1][C:2]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][C:5]([C:6]([NH:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=O)=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22].Cl>O1CCCC1.C1(C)C=CC=CC=1>[OH:1][C:2]1[C:16]([C:17]([CH3:19])([CH3:18])[CH3:20])=[CH:15][C:5]([CH2:6][NH:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH3:14])=[CH:4][C:3]=1[C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1nccn1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nccn1NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A suspension of 200 mg of 1-(4-hydroxy-3,5-di-tert.-butylbenzoylamino)-2-methyl-1H-imidazole in 10 ml of anhydrous tetrahydrofuran is treated under an inert gas with 1.2 ml of a 2N borane-dimethyl sulfide complex solution in toluene. The mixture is then heated at reflux for 4 hours, left to cool to 0°, treated with methanolic hydrochloric acid (5 ml of methanol and 0.5 ml of conc. HCl), and again heated at reflux for 1 hour and evaporated in a vacuum. The residue is taken up in 4 ml of water and saturated sodium bicarbonate solution is added until the pH amounts to 8-9. The mixture is extracted three times with 5 ml of methylene chloride each time and, after drying, the combined methylene chloride phases are evaporated. The residue is recrystallized from cyclohexane and there is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-2-methylimidazole of m.p. 180°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25](OC(C)=O)=[O:26]>N1C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH2:15][NH:16][C:25](=[O:26])[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCC(c1ccccc1Cl)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To 4-[2-Amino-1-(2-chloro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (201) (0.75 g, 2.21 mmol) in pyridine (5 mL) was added Ac2O (5 mL). The reaction was allowed to stir at 60° C. for 1 h and then allowed to cool to room temperature. The reaction mixture was diluted with EtOAc (100 mL) and washed with sat. NaHCO3 (100 mL)), H2O (100 mL) and brine (100 mL). The organic phase was concentrated to dryness yielding 0.85 g (99%) product.