Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([NH2:14])[N:13]=[C:9]3[CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[CH:6]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH3:25][N:26]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH3:27]>ClCCl>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[C:12]([NH:14][C:33](=[O:34])[C:32]4[CH:36]=[CH:37][C:29]([CH2:28][N:26]([CH3:25])[CH3:27])=[CH:30][CH:31]=4)[N:13]=[C:9]3[CH:8]=[C:7]([C:15]([F:16])([F:17])[F:18])[CH:6]=2)[CH2:2][CH2:3]1
Reactant: CN(C)Cc1ccc(C(=O)Cl)cc1
Reactant: Nc1nc2cc(C(F)(F)F)cc(NC3CC3)n2n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)Cc1ccc(C(=O)Nc2nc3cc(C(F)(F)F)cc(NC4CC4)n3n2)cc1
Yield: 51.9 %

Procedure:
To a reaction vessel containing N5-cyclopropyl-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A18), 77 mg, 0.3 mmol, 1 eq.) and pyridine (0.063 mL, 1.2 mmol, 4 eq.) in dichloromethane (1 mL) was added 4-dimethylaminomethyl-benzoyl chloride (118 mg, 0.6 mmol, 2 eq.) as a solution in dichloromethane (2 mL), dropwise. The vessel was capped and heated to reflux for approximately 16 hours. The reaction mixture was cooled and the solvent removed in vacuo. The residue dissolved in DMSO (1.5 mL) and purified by reverse phase preparatory HPLC to give the title compound as a white solid (65.1 mg, 52%). HPLC, Rt: 2.59 min (purity: 100%). LC/MS M+(ESI): 419.2, M−(ESI) 417.2.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[S:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.C(O)(=[O:32])C>O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([S:24](=[O:27])(=[O:26])[NH2:25])[C:16]=1[S:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:32])[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1cc(CO)cc(NCc2ccccc2)c1Sc1ccccc1
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: NS(=O)(=O)c1cc(CO)cc(NCc2ccccc2)c1S(=O)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 3-benzylamino-4-phenylthio-5-sulfamylbenzyl alcohol (8.0 g; prepared as described in Example 24), hydrogenperoxide (10 ml, 30% in water) and acetic acid (80 ml) is stirred at 22°-25° C. for 24 hours. The resulting solution is diluted with water (40 ml) and cooled to precipitate crude 3-benzylamino-4-phenylsulfinyl-5-sulfamylbenzyl alcohol. After recrystallization from a mixture of ethanol and 2-methoxyethanol it is obtained with a melting point of 213°-214° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[C:5]([NH2:14])[NH:4][N:3]=1.[CH3:15][C:16]1[CH:17]=[C:18]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])[CH:19]=[CH:20][CH:21]=1>N1C=CC=CC=1>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([CH3:1])=[N:3][N:4]3[C:22]([C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[CH:17]=4)=[CH:23][C:24](=[O:25])[NH:14][C:5]=23)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CC(=O)c1cccc(C)c1
Reactant: Cc1ccc(-c2c(C)n[nH]c2N)cc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(C)nn3c(-c4cccc(C)c4)cc(=O)[nH]c23)cc1
Temperature: 25 °C

Procedure:
3-Methyl-4-(4-methylphenyl)-1H-pyrazol-5-amine and ethyl 3-(3-methylphenyl)-3-oxopropanoate are stirred overnight in a pyridine (10 mL) solvent at 95° C. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1(C)C=CC=CC=1>[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: COc1ccc(Cl)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccccc2C)cc1
Yield: 100.9 %

Procedure:
4-Chloroanisole (74 mg, 0.52 mmol) reacted with 2-methylphenylboronic acid (102 mg, 0.75 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (87 mg, 1.50 mmol) in toluene at 80° C. to give the title compound (104 mg, 99%) as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 7.35-7.31 (m, 6H), 7.04 (d, 2H, J=8.8 Hz), 3.92 (s, 3H), 2.37 (s, 3H). 13C{1H}-NMR (125 MHz, CDCl3): δ 158.43, 141.47, 135.40, 134.28, 130.25, 130.19, 129.85, 126.91, 125.71, 113.41, 55.19, 20.52. GC/MS(EI): m/z 198 (M+).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH:7][C:8]1(CO)[CH:14]=[CH:13][C:12]2[CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1>O1CCOCC1.O>[O:7]=[C:8]1[CH:14]=[CH:13][C:12]2[CH:15]=[C:16]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C=CC(O)(CO)CO2
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(c1)C=CC(=O)CO2
Yield: 45 %

Procedure:
116 mg (0.54 mmol) of sodium periodate are added at ambient temperature in 4 equal portions, every quarter of an hour, to 135 mg (0.54 mmol) of methyl 3-hydroxy-3-(hydroxymethyl)-2,3-dihydro-1-benzoxepin-7-carboxylate, prepared according to example 45, in solution in 16 ml of a 3/1 dioxane/water mixture. After the usual treatments, the crude reaction product is purified by chromatography on silica gel (ethyl acetate/heptane 25/75) to give 53 mg (45%) of methyl 3-oxo-2,3-dihydro-1-benzoxepin-7-carboxylate in the form of a white solid; M.p.=98° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH:27]=[CH:26]1.Cl>CN(C=O)C.C(OCC)(=O)C>[NH2:8][C:5]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:3]([CH2:2][NH:1][C:25]([CH:26]=[CH:27][C:28]([OH:30])=[O:29])=[O:31])=[N:7][N:6]=1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC1=NN=C(CNC(=O)C=CC(=O)O)C1=NNc1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
5-Aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg, 0.25 mmole) was dissolved in 3 mL of anhydrous DMF. To this solution was added triethylamine (0.51 mmole, 52 mg) and then a solution of maleic anhydride (30.2 mg, 0.31 mmole) in 1 mL of DMF. The reaction mixture was stirred at ambient temperature for 30 minutes and then worked up by the addition of saline and ethyl acetate. The mixture was acidified with 1 mL of 1.5 M HCl. The aqueous phase was extracted with ethyl acetate. The combined organic layer was washed with saline three times and dried over anhydrous MgSO4. The solution was then filtered, concentrated and purified by preparative TLC (CH2Cl2:MeOH:trace acetic acid=6:1) to yield 58 mg of the title compound as a yellow powder. MS (m/z, ES−): 331 (M−1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) □δ 11.90 (br s, 1H), 7.35-7.70 (m, 3H), 7.30 (br s, 2H), 6.12 (d, 1H), 5.70 (d, 1H), 4.52 (s, 2H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.C([O:23][C:24]1[C:25](=[O:35])[C:26](=O)[C:27]=1[NH:28][C:29]([CH3:33])([CH3:32])[CH2:30][CH3:31])CCC>O1CCCC1>[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][NH:6][C:26]1[C:25](=[O:35])[C:24](=[O:23])[C:27]=1[NH:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH3:31]
Reactant: CCCCOc1c(NC(C)(C)CC)c(=O)c1=O
Reactant: NCc1c(Cl)cccc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(C)(C)Nc1c(NCc2c(Cl)cccc2Cl)c(=O)c1=O
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To 2,6-dichlorobenzylamine hydrochloride of Example 4, Step 2 (1.06 g 5.0 mmol) in tetrahydrofuran (10 mL) was added triethyl amine (0.505 g, 5.0 mmol) followed by 3-butoxy-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (1.20 g, 5.0 mmol, Example 3) and stirring was continued at room temperature for approximately 16 hours. The reaction mixture was freed of solvent and the residue was triturated successively with water and with diethyl ether, and then dried. The resulting light yellow solid was recrystallized from acetonitrile three times to provide 0.755 g (44%) of the title compound as a white solid: mp 239°-241° C. (dec); 1H NMR (DMSO-d6): δ7.57 (m, 1H), 7.55 (m, 1H), 7.52 (br m, 1H),m 7.43 (m, 1H), 7.30 (s, br, 1H), 5.07 (d, 2H), 1.65 (q, 2H), 1.28 (s, 6H), 0.80 (t, 3H) ppm. IR (KBr): 3250, 1785, 1660 cm-1 ; MS (m/z) 340/342/344 (M+). HPLC indicates a major component (99.7%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25](=[O:37])[C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])=[CH:28][CH:27]=3)=[N:23][C:18]2=[CH:17][CH:16]=1>>[OH:34][CH2:33][C:32]([C:29]1[CH:30]=[CH:31][C:26]([C:25]([NH:24][C:22]2[S:21][C:19]3[C:18]([N:23]=2)=[CH:17][CH:16]=[C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[O:4])[NH:2][CH3:1])=[CH:6][CH:7]=2)[N:20]=3)=[O:37])=[CH:27][CH:28]=1)([CH3:36])[CH3:35]
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CNC(=O)c1ccc(-c2ccc3nc(NC(=O)c4ccc(C(C)(C)CO)cc4)sc3n2)cc1
Yield: 15 %

Procedure:
The titled compound (yield=15%, white solid) was prepared using a procedure analogous to that described in connection with 9 (Example 9) except 4-(methylcarbamoyl)phenylboronic acid and 2F (Example 2) were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 2.82 (d, J=4.55 Hz, 3H) 3.49 (d, J=5.31 Hz, 2H) 4.75-4.81 (m, 1H) 7.58 (d, J=8.84 Hz, 2H) 7.98 (d, J=8.59 Hz, 2H) 8.11 (d, J=8.84 Hz, 2H) 8.17-8.22 (m, 1H) 8.22-8.28 (m, 3H) 8.56 (q, J=4.63 Hz, 1H) 13.02 (s, 1H); ESI-MS: m/z 461.0 (M+H)+.
Reaction SMILES: [CH2:1]([S:4][C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]=[CH2:3].[C:24](O)([CH3:27])([CH3:26])C.C[C:30]([CH3:33])([O-])[CH3:31]>O1CCCC1>[CH:19](/[C:12]1([CH:13]=[CH:14][CH:15]=[CH:16][CH2:17]1)[C:5]([S:4][C:1]([C:26]1[CH:24]=[CH:27][CH:12]=[CH:5][CH:6]=1)([C:31]1[CH:30]=[CH:33][CH:3]=[CH:2][CH:1]=1)[C:2]1(/[CH:13]=[CH:14]/[CH3:15])[CH:7]=[CH:8][CH:9]=[CH:10][CH2:3]1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[CH:18]\[CH3:23]
Reactant: C=CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)O
Solvent: C1CCOC1
Product: C/C=C/C1(C(SC(c2ccccc2)(c2ccccc2)C2(/C=C/C)C=CC=CC2)(c2ccccc2)c2ccccc2)C=CC=CC1

Procedure:
Then, 12.64 g of allyl tritylsulfide was dissolved in a solvent mixture consisting of 130 ml of t-butanol and 70 ml of tetrahydrofuran, and 9.0 g of pottasium tert. -butoxide was added to the resulting solution at room temperature with stirring, and the mixture was further stirred for 15 hours. The solvents were removed from the reaction mixture at a temperature of below 40° C. by distillation under reduced pressure, and then 200 ml of water and 400 ml of benzene were added to the residue to extract. The benzene layer was washed with water and dried over anhydrous magnesium sulfate. Then, the solvent was removed therefrom by distillation under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with n-hexane, whereby 5.0 g of trans 1-propenyl tritylsulfide (melting point: 105°-106° C.) was obtained as colorless crystal.
Reaction SMILES: [C:1]1(=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.COP([CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH3:27])=O)(=O)OC.O.[NH2:29][NH2:30]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]2[N:30]=[N:29][C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:1]=3[CH:17]=2)=[C:21]([CH3:27])[CH:22]=1
Reactant: NN
Reactant: COP(=O)(CC(=O)c1ccc(Cl)cc1C)OC
Reactant: O=C1CCCCCCC1=O
Solvent: O
Product: Cc1cc(Cl)ccc1-c1cc2c(nn1)CCCCCC2

Procedure:
light yellow solid. MS (EI): 286.1 (M+). Prepared from cyclooctane-1,2-dione, [2-(4-Chloro-2-methyl-phenyl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=O)[C:2]2=O.COP([CH2:17][C:18](=O)[CH2:19][C:20]1([CH3:23])[CH2:22][CH2:21]1)(=O)OC.O.[NH2:26][NH2:27]>>[CH3:23][C:20]1([CH2:19][C:18]2[N:26]=[N:27][C:2]3[CH:1]4[CH2:8][CH2:7][CH:4]([C:3]=3[CH:17]=2)[CH2:5][CH2:6]4)[CH2:22][CH2:21]1
Reactant: NN
Reactant: O=C1C(=O)C2CCC1CC2
Reactant: COP(=O)(CC(=O)CC1(C)CC1)OC
Solvent: O
Product: CC1(Cc2cc3c(nn2)C2CCC3CC2)CC1

Procedure:
Light-yellow solid MS (ESI): 229.2 (MH+). Prepared from bicyclo[2.2.2]octane-2,3-dione, [3-(1-methyl-cyclopropyl)-2-oxo-propyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][CH2:8][CH:9]=O)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][NH:25][CH2:26]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH2:23][CH2:24][N:25]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]3[C:4](=[O:11])[C:3]4=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]4[C:1]3=[O:16])[CH2:26]2)=[CH:21][CH:20]=1
Reactant: COc1ccc2c(c1)CNCC2
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Product: COc1ccc2c(c1)CN(CCCCN1C(=O)c3ccccc3C1=O)CC2

Procedure:
Prepared from 4-phthalimidobutyraldehyde (15.96 g, 0.074 mol) and 7-methoxy-1,2,3,4-tetrahydroisoquinoline (10 g, 0.061 mol) using a procedure similar to that of Example 1 (13.5 g, 60%).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[N:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH:22]=O.N1CCCCC1.CCOC(C)=O>CCO>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11]([C:12]2[C:13]([CH3:14])=[N:19][C:20]3[C:21]([CH:22]=2)=[C:24]([CH3:28])[CH:25]=[CH:26][N:27]=3)=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccnc(N)c1C=O
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1nc2nccc(C)c2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C

Procedure:
In a screw cap pressure tube were N-(4-tert-butylbenzyl)-3-oxobutanamide (94.5 mg, 0.38 mmol), 2-amino-4-methylnicotinaldehyde (52.0 mg, 0.38 mmol) and piperidine (151.0 μl, 1.53 mmol) suspended in EtOH (0.5 ml). The tube was sealed and the mixture heated to 120° C. for 1.5 h. The mixture was allowed to cool. EtOAc was added and the mixture washed with H2O, dried (MgSO4), filtered and concentrated. The crude product was purified by flash chromatography CH2Cl2/MeOH 96/4 yielding 61.5 mg of the title compound (47%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1.C(N(CC)CC)C>C1COCC1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(C(=O)Nc2ccc(C(=O)c3ccccc3)cc2)c1
Yield: 94.1 %

Procedure:
Reaction of 4-aminobenzophenone (100 mg, 0.51 mmol) in THF (6 mL) with m-anisoyl chloride (136 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave N-(4-benzoyl-phenyl)-3-methoxy-benzamide (160 mg, 0.48 mmol, 94% yield) as a white powder after purification by chromatography on silica gel (eluent EtOAc/DCM 0/100 to 5/95.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]2[C:5]([CH2:6][CH2:7][CH:8]3[C:12](O)([C:13]4[O:17][N:16]=[C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:14]=4[C:24]([F:27])([F:26])[F:25])[O:11][N:10]=[C:9]32)=[CH:4][C:3]=1[C:31]([O:33][CH3:34])=[O:32].N1C=CC=CC=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:30]=[C:29]2[C:5]([CH2:6][CH2:7][C:8]3[C:9]2=[N:10][O:11][C:12]=3[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:14]=2[C:24]([F:27])([F:26])[F:25])=[CH:4][C:3]=1[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)c1cc2c(cc1F)C1=NOC(O)(c3onc(-c4ccccc4)c3C(F)(F)F)C1CC2
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(cc1F)-c1noc(-c3onc(-c4ccccc4)c3C(F)(F)F)c1CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.8 %

Procedure:
To a stirred suspension of methyl 8-fluoro-3-hydroxy-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-3,3a,4,5-tetrahydronaphtho[1,2-c]isoxazole-7-carboxylate (Preparation 67B, 0.055 g, 0.115 mmol) in anhydrous toluene (1.0 mL) at room temperature was added pyridine (0.2 mL) followed by thionyl chloride (0.014 mL, 0.196 mmol). The reaction mixture was stirred at room temperature for 15 min. and then at 80° C. for 15 min. The reaction mixture was cooled to room temperature and concentrated. The solid residue was partitioned between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The dichloromethane extract was collected and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded methyl 8-fluoro-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carboxylate [0.050 g, 0.109 mmol, 94%] as an off white solid product. The product had an HPLC ret. time=3.28 min. (condition B). LC/MS M+1=459.1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.N1C2C=CC=C(N)C=2C=N1.[F:28]C1C=CC(I)=CC=1>>[F:28][C:6]1[CH:5]=[CH:4][C:3]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)=[CH:2][CH:7]=1
Reactant: Nc1cccc2c1cnn2-c1ccccc1F
Reactant: Fc1ccc(I)cc1
Agent: Nc1cccc2[nH]ncc12
Product: Nc1cccc2c1cnn2-c1ccc(F)cc1

Procedure:
Similarly prepared to Intermediate 1 from 1H-indazol-4-amine and 4-fluoro-1-iodobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=CC(S(Cl)(=O)=O)=C[CH:21]=1.C(O)(C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:20]([CH3:30])([CH3:25])[CH3:21])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 88.7 %

Procedure:
To 4-chloro-2-nitrobenzoic acid (262 g) in a pyridine (1.3 liter) solution, p-toluenesulfonyl chloride (272.6 g) was slowly added at room temperature, and the mixture was stirred at that temperature for 15 minutes. To the reaction solution, tert-butyl alcohol (249 ml) was added dropwise, then the mixture was stirred for 5 hours. To the reaction mixture toluene (1 liter) was added, and the mixture was stirred for 1.5 hours, then the precipitate were removed by filtration. The filtrate was concentrated, ethyl acetate (1.3 liter) was added to the residue, the mixture was successively washed with water, saturated aqueous potassium hydrogensulfate solution, aqueous saturated sodium hydrogencarbonate solution, and brine, then the organic layer was dried over anhydrous sodium sulfate, then concentrated. Methanol (470 ml) was added to the residue, and after the precipitation of the crystals was confirmed, water (142 ml) was added. The mixture was stirred under ice cooling for 1.5 hours, then the crystals were collected by filtration. The same recrystallization procedure as the above was performed again to obtain the title compound (297 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)=[O:3].[CH:21]1([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[CH:14]1([CH2:13][C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH2:24][CH:21]4[CH2:23][CH2:22]4)[CH2:26][CH2:27]3)=[O:3])=[CH:6][CH:7]=2)=[O:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CN(CC2CC2)CCN1
Reactant: O=C(CC1CCCCC1)Nc1ccc(OC(=O)Cl)cc1
Product: O=C(CC1CCCCC1)Nc1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1

Procedure:
The title compound was prepared from 4-(2-cyclohexyl-acetylamino)-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, preparative HPLC (method C (60%, off-white crystals). HPLC-MS m/z=400.3 (M+1), Rt: 2.42 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[Br:11].[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](O)=[CH:17][CH:16]=1)[CH3:14].C(=O)([O-])[O-:23].[K+].[K+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:23][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:13][CH3:14])=[CH:6][C:5]=1[Br:11]
Reactant: CCc1ccc(O)cc1
Reactant: COC(=O)c1ccc(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCc1ccccc1Oc1ccc(C(=O)OC)c(Br)c1
Temperature: 160 °C
Reaction time: 16 h
Yield: 64.9 %

Procedure:
To a solution of 2-bromo-4-fluoro-benzoic acid methyl ester (488 mg, 2.09 mmol) in anhydrous DMF (15 ml), 4-ethylphenol (256 mg, 2.09 mmol) and potassium carbonate (289 mg, 2.09 mmol) were added at room temperature, followed by stirring under a nitrogen atmosphere for 16 hours at 160° C. The reaction mixture was cooled and, after addition of saturated aqueous ammonium chloride, was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:20)) to give the titled compound (455 mg, 65%).
Reaction SMILES: [F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=S)[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4].IC.[N+:30]([CH3:33])([O-:32])=[O:31].[H-].[Na+]>O1CCCC1>[F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[CH:33][N+:30]([O-:32])=[O:31])[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: FCC1(CF)C=C(N2CCCC2=S)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: O=[N+]([O-])C=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 11.7 %

Procedure:
To a mixture of 0.16 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-thioxo-1-pyrrolidinyl)-2H-1-benzopyran, 0.78 g of iodomethane, 0.41 g of nitromethane and 6 ml of tetrahydrofuran was added 0.10 g of sodium hydride (60%) at room temperature with stirring. The mixture was refluxed with heating for 2 hours. After addition of ice water, the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.02 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-nitromethylene-1-pyrrolidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 195°-197° C.