Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=O.[CH:19]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:22]12[N:25]([C:26]3[CH:32]=[CH:31][C:29]([NH:30][C:16]([C:3]4[C:2](=[O:1])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][C:10]=5[C:12]([F:13])([F:14])[F:15])[NH:5][CH:4]=4)=[O:18])=[C:28]([C:33]([F:36])([F:34])[F:35])[CH:27]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:24][CH2:23]2
Reactant: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 65 °C

Procedure:
To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid (7) (9.1 g, 35.39 mmol) and 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (11A) (9.2 g, 35.74 mmol) in 2-methyltetrahydrofuran (91.00 mL) was added propyl phosphonic acid cyclic anhydride (T3P (50% solution in ethyl acetate), 52.68 mL, 88.48 mmol) and pyridine (5.6 g, 5.73 mL, 70.78 mmol) at room temperature. The reaction flask was heated at 65° C. for 10 h under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was then diluted with ethyl acetate and quenched with saturated Na2CO3 solution (50 mL). The layers were separated, and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated to a tan solid. The crude solid was slurried in a 2:1 mixture of ethyl acetate and diethyl ether, collected by vacuum filtration, and washed twice more with ethyl acetate/diethyl ether mixture to provide the crude product as a light yellow crystalline powder. The powder was dissolved in warm ethyl acetate and absorbed onto Celite. Purification by silica gel chromatography (0-50% ethyl acetate in dichloromethane) provided N-(4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)phenyl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (Compound I) as a white crystalline solid in the solid form A. LC/MS m/z 496.0 [M+H]+, retention time 1.48 min (RP-C18, 10-99% CH3CN/0.05% TFA over 3 min). 1HNMR (400.0 MHz, DMSO-d6) δ 13.08 (s, 1H), 12.16 (s, 1H), 8.88 (s, 1H), 8.04 (dd, J=2.1, 7.4 Hz, 1H), 7.95-7.88 (m, 3H), 7.22 (dd, 2.5, 8.9 Hz, 1H), 7.16 (d, J=2.5 Hz, 1H), 4.33 (s, 2H), 1.67 (d, J=6.9 Hz, 4H), 1.44 (d, J=6.9 Hz, 4H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:27][CH2:28][CH2:29][C:30]([CH3:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:42][C:30]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([CH2:29][CH2:28][CH2:27][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:11]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:3][CH2:2]1)[CH2:31][C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CC(C)(CCCBr)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(C)(CCCN1CCC(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
0.611 g (1.75 mmol) of 4′-trifluoromethyl-biphenyl-2-carboxylic acid-piperidin-4-yl-amide, 0.5 g (1.75 mmol) of methyl 5-bromo-2-methyl-2-phenyl-pentanecarboxylate and 0.8 g (5.7 mmol) of potassium carbonate are dissolved in 50 ml dimethylformamide and mixed with water. The mixture is stirred for 72 hours at 90° C. Then the reaction mixture is poured onto water, the precipitate is filtered off and dried. After column chromatography on silica gel (eluant: ethyl acetate) colourless crystals are left.
Reaction SMILES: [Cl:1][C:2]1([Cl:14])[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1(C)[CH:11]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C1C=CC=CC=1>[Cl:1][C:2]1([Cl:14])[CH:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:3]1[CH3:11].[CH2:2]=[N:26][C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C=O)C(c2ccccc2)C1(Cl)Cl
Reactant: CC(C)(C)N
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=NC(C)(C)C
Product: CC1C(c2ccccc2)C1(Cl)Cl
Yield: 159.4 %

Procedure:
1.3 g (0.0057 mol) of 2,2-dichloro-1-methyl-3-phenylcyclopropane carbaldehyde were dissolved in 16 ml of anhydrous benzene. The resulting benzene solution was admixed with 0.5 g of anhydrous sodium sulfate, and stirred. To the benzene solution was dropwise added a solution of 2.0 g (0.027 mol) of t-butylamine in 4 ml of the same solvent over 15 minutes. After further stirring for 94 hours, the reaction mixture was filtered to remove the inorganic substances therefrom. Then the benzene and the t-butylamine were distilled off under a reduced pressure to obtain 1.3 g of 2,2-dichloro-1-methyl-3-phenylcyclopropane-methylidene-t-butylamine as an oily substance with light yellow color. Yield: 81%.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.CCOC(C)=O.[Fe]>[NH2:1][C:4]1[C:5]([N:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCC3)C1
Temperature: 80 °C
Yield: 127.8 %

Procedure:
A mixture of tert-butyl [(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (43 mg, 0.12 mmol), iron powder (106 mg, 1.90 mmol) and NH4Cl (127 mg, 2.37 mmol) in EtOH (0.69 mL) and water (0.11 mL) was heated in a sealed tube at 80° C. for 1 h. The mixture was diluted with EtOAc and the resulting solution was washed with saturated aq. Na2CO3, dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound as a brown-orange powder (51 mg, 100%). LCMS calc. for C18H29N4O2 (M+H)+: m/z=333.2. Found: 333.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([Cl:14])[CH:3]=1.C(N(CC)CC)C.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.[O:34]1[CH2:38][CH2:37][CH:36]([O:39][C:40]2[CH:41]=[C:42]([CH:44]=[CH:45][CH:46]=2)[NH2:43])[CH2:35]1>ClCCl>[Cl:14][C:4]1[CH:3]=[C:2]([NH:1][C:23]([NH:43][C:42]2[CH:44]=[CH:45][CH:46]=[C:40]([O:39][CH:36]3[CH2:37][CH2:38][O:34][CH2:35]3)[CH:41]=2)=[O:25])[CH:7]=[CH:6][C:5]=1[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1ccc(N)cc1Cl
Reactant: Nc1cccc(OC2CCOC2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2cccc(OC3CCOC3)c2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
To a solution of ethyl 2-(4-amino-2-chlorophenyl)acetate (240 mg, 1.12 mmol) in dry dichloromethane (4 mL), was added triethylamine (3.13 mL, 22.47 mmol) followed by triphosgene (333 mg, 1.12 mmol) solution in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 h. To this mixture was then added 3-(tetrahydrofuran-3-yloxy)aniline (403 mg, 2.25 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 4 h and concentrated. The residue was dissolved in ethyl acetate and washed with water (2×20 mL), brine (10 mL), dried and concentrated. The crude product was purified by flash column chromatography to afford the desired product as a clear oil (221 mg, 0.528 mmol, 47%). 1H NMR: 1.30 (t, 3H, J=7.2 Hz), 2.05-2.15 (m, 2H), 3.68 (s, 2H), 3.81-3.97 (m, 4H), 4.21 (q, 2H, J=7.2 Hz), 4.82 (d, 1H, J=1.6 Hz), 6.49 (dd, 1H, J=8 Hz, 1.6 Hz), 6.71 (d, 1H, J=7.6 Hz), 7.02-7.11 (m, 4H), 7.18 (s, 1H), 7.53 (s, 1H), 7.59 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[O:14]1[CH2:19][CH2:18][O:17][C:16]2[C:20]([CH:24]=O)=[CH:21][CH:22]=[CH:23][C:15]1=2>>[O:14]1[CH2:19][CH2:18][O:17][C:16]2[C:20]([CH:24]3[N:11]([CH2:10][C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=4)[C:15](=[O:14])[CH:16]([OH:17])[CH2:20]3)=[CH:21][CH:22]=[CH:23][C:15]1=2
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=Cc1cccc2c1OCCO2
Product: O=C1C(O)CC(c2cccc3c2OCCO3)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B) and 10F (GP10F) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and commercially available 2,3-dihydrobenzo[b][1,4]dioxine-5-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 409.94 g/mol.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[CH2:13][CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2].[C:29]([O-])(=O)C.[Na+].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.C(OCOCC)C>[C:1]([O:4][CH2:5][C:6](=[O:28])[C@:7]1([OH:27])[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([CH2:22][CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:26])[CH2:17][CH2:18]2)[C:13](=[CH2:29])[CH2:12]3)[CH2:9][CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [Na+]
Solvent: CCOCOCC
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC[C@]3(O)C(=O)COC(C)=O)[C@@]2(C)CCC(=O)C=C12
Yield: 86.3 %

Procedure:
Analogously to Example 35, 1.0 g of 21-acetoxy-17α-hydroxy-4-pregnene-3,20-dione is stirred with a suspension of 1.0 g of sodium acetate in 30 ml of chloroform, 30 ml of formaldehyde diethylacetal, and 3.8 ml of phosphorus oxychloride for 7 hours at 65° C., and then worked up. The crude product is purified on 220 g of silica gel with a methylene chloride/acetone gradient (0-12% acetone), thus obtaining 890 mg of 21-acetoxy-17α-hydroxy-6-methylene-4-pregnene-3,20-dione, mp 194.5°-196° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35]3[CH:41]=[C:40]([C:42]([O-])=[O:43])[CH:39]=[CH:38][C:36]=3[N:37]=2)=[CH:29][CH:28]=1>>[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35]3[CH:41]=[C:40]([C:42]([NH:22][C:20]4[CH:19]=[CH:18][C:16]5[NH:17][C:13]([C:10]6[CH:11]=[CH:12][C:7]([N:4]7[CH2:5][CH2:6][O:1][CH2:2][CH2:3]7)=[CH:8][CH:9]=6)=[N:14][C:15]=5[CH:21]=4)=[O:43])[CH:39]=[CH:38][C:36]=3[N:37]=2)=[CH:31][CH:32]=1
Reactant: O=C([O-])c1ccc2nc(-c3ccc(OCCO)cc3)[nH]c2c1
Reactant: Nc1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccc2nc(-c3ccc(OCCO)cc3)[nH]c2c1

Procedure:
Compound 299 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinophenyl)-5-aminobenzimidazole and 2-(4-(2-hydroxyethoxy)phenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C33H30N6O4: 575.23; found: 575.07.
Reaction SMILES: [CH:1]1([C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:15][CH:14]=1>CS(C)=O.[Cl-].[Na+].O>[CH:1]1([C:4](=[O:8])[CH:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N+:25]([O-:27])=[O:26])=[CH:17][CH:18]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Reactant: N#CCC(=O)C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC(Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1)C(=O)C1CC1
Reaction time: 1 h
Yield: 33.6 %

Procedure:
To a solution of 2.61 g (24.0 mmol) 3-cyclopropyl-3-oxopropanenitrile in 150 mL DMSO was added 1.01 g (25.2 mmol) 60% NaH in oil. After 1 hour, 3.50 g (12.0 mmol) 4'-bromomethyl-2-nitrobiphenyl was added all at once to the solution. After 3 hours, the solution was poured into brine and extracted 3 times with ether. The combined organic material was dried over MgSO4, stripped of solvent in vacuo, and was chromatographed on silica gel under medium pressure using 3/40/57 EtOAc/CH2Cl2/hexanes to give 1.29 g (34% yield) of the title compound as a yellow glass. Rf 0.13 in 3/40/57 EtOAc/CH2Cl2/hexanes, visualized by UV and ammonium molybdate/ceric sulfate stain; Rf of the dialkylated material is 0.19 in the same solvent mixture.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[C:25]([F:28])([F:27])[F:26]>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[C:25]([F:26])([F:27])[F:28])=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(O)cc1C(F)(F)F
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: O=C(Nc1ccc(O)cc1C(F)(F)F)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-amino-3-(trifluoromethyl)phenol (prepared according to the method described by Filler, R.; Novar, H. J. in Org. Chem. 1961, 26, 2707-2710”), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([CH3:19])[C:4]=1[NH:20][C:21]([C:23]1[CH:37]=[CH:36][C:26]([CH2:27][NH:28]C(=O)OC(C)(C)C)=[C:25]([CH3:38])[CH:24]=1)=[O:22])[CH3:2].Cl>C(O)C.C(OCC)(=O)C.O.C([O-])(O)=O.[Na+]>[NH2:28][CH2:27][C:26]1[CH:36]=[CH:37][C:23]([C:21]([NH:20][C:4]2[C:5]([CH3:19])=[CH:6][C:7]([C:9]([F:18])([C:14]([F:15])([F:16])[F:17])[C:10]([F:11])([F:12])[F:13])=[CH:8][C:3]=2[CH2:1][CH3:2])=[O:22])=[CH:24][C:25]=1[CH3:38]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(CN)c(C)c1
Temperature: 60 °C

Procedure:
Tert-Butyl (4-{[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-carbamoyl}-2-methylbenzyl)carbamate (1.7 g) was dissolved in ethanol (30 ml). To the solution, conc. hydrochloric acid (3 ml) was added and the mixture was stirred under heating at 60° C. for 4 hours. After adjusting to room temperature, the reaction solution was diluted with ethyl acetate and water and neutralized with sodium hydrocarbonate under vigorous stirring. The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain 4-(aminomethyl)-N-[2-ethyl-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)-6-methylphenyl]-3-methyl benzamide as a crude product (0.81 g). Without further purification, the crude product was used for the next reaction.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[OH:10].[C:11](OC)(OC)(OC)C>S(=O)(=O)(O)O>[O:9]1[C:8]2=[CH:7][CH:6]=[CH:5][C:4]([OH:10])=[C:3]2[N:2]=[CH:11]1
Reactant: Nc1c(O)cccc1O
Reactant: COC(C)(OC)OC
Agent: Cl
Agent: O=S(=O)(O)O
Product: Oc1cccc2ocnc12
Reaction time: 8 h
Yield: 51 %

Procedure:
A mixture of 2-amino-benzene-1,3-diol hydrochloride (2.00 g, 12.4 mmol) and trimethyl orthoacetate (15 mL) was treated with concentrated sulfuric acid (5 drops) and the resulting mixture heated at reflux for 3 h, cooled and allowed to stand at room temperature overnight. The resulting mixture was concentrated in vacuo and the residue treated with ethyl acetate (200 mL), washed with water (200 mL) and brine (100 mL). The combined aqueous phases were extracted with ethyl acetate (200 mL) and the combined organic phases washed with brine and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo which afforded benzooxazol-4-ol (0.94 g, 51%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl.N1C=CC=CC=1>[CH3:25][S:26]([NH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:7](/[CH:9]=[CH:10]/[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1)(=[O:28])=[O:27]
Reactant: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
To a stirred solution of (E)-5-amino-1-(2-pyridyl)-2-styryl-1H-benzimidazole (162 mg, 0.52 mmol) in dichloromethane (3 ml) and pyridine (1 ml) was added a solution of methanesulfonyl chloride (63 mg, 0.55 mmol) in dichloromethane (2 ml) dropwise. The reaction mixture was stirred for 2 h at room temperature and then partitioned between ethyl acetate (50 ml) and saturated aqueous sodium bicarbonate solution (50 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 ml). The combined extracts were washed with brine (50 ml), dried (sodium sulfate) and concentrated in vacuo to give brown oil. It was purified by column chromatography (silica gel, 20 g; n-hexane/ethyl acetate (5/1)). Recrystallization of the residue from ethyl acetate afforded 70 mg (34%) of the titled compound as off white solids.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>O1CCCC1>[N+:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[S:3][C:4]=2[CH:10]=1)([O-:13])=[O:12]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)sc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.40 mmol 2-chloro-6-nitrobenzothiazole (CA=[2407-11-6]), 4.19 mmol of piperazine and 4.19 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 10 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a yellow solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.O.[NH2:30][NH2:31].O>CN(C=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:31][N:30]=2)=[CH:22][CH:23]=1
Reactant: O=C(Cc1ccc(F)cc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccc(F)cc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 130 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-fluorophenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (3.2 g, 8.5 mmol, prepared in Synthetic Example 27) in DMF (50 ml) was added hydrazine monohydrate (80%, 1.2 ml, 30 mmol, 3.5 eq.), and the mixture was then stirred at 130° C. for 2 hours. The reaction mixture was admixed with water to precipitate crystals, allowed to stand until it was cooled, filtered off, washed with water, and dried to give 3-(4-fluorobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (3.1 g, 98%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:12][C:13](O)=[O:14].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[CH:11]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:12][C:13]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:14]
Reactant: O=C(O)CC(c1ccccc1)N1Cc2ccccc2C1=O
Reactant: Nc1ccccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(c1ccccc1)N1Cc2ccccc2C1=O)Nc1ccccn1

Procedure:
3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-propionic acid (0.42 mmol, 1 eq), 2-amino pyridine (1.5 eq), HBTU [2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphat], (1.5 eq) and N-ethyl diisopropylamine (1.5 eq) are suspended in chloroform and reacted in the microwave (90 min, 120° C., Emrys Optimizer). The resulting mixture is partitioned between chloroform and water. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. The crude product is dissolved in DMSO and purified by prep. LC/MS (reversed phase). 3-(1-Oxo-1,3-dihydro-isoindole-2-yl)-3-phenyl-N-pyridine-2-yl-propionamide (“A1”) is obtained as brown solid (36% yield); ES-MS (MH+)=358.2; 1H-NMR (DMSO-d6, 400 MHz): δ [ppm] 10.72 (s, 1H), 8.29 (d, 1H, 4.8 Hz), 7.97 (d, 1H, 8.3 Hz), 7.73-7.27 (m, 10H), 7.08-7.05 (m, 1H), 5.95-5.92 (m, 1H), 4.62 (d, 1H, 17.5 Hz), 4.18 (d, 1H, 17.5 Hz), 3.39-3.32 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17])([O-:3])=[O:2].[CH3:20][NH:21][CH3:22].C(O)(=O)C>O>[CH3:20][N:21]([CH3:22])[S:16]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:4]=1[N+:1]([O-:3])=[O:2])[NH:11][C:10](=[O:14])[C:9](=[O:15])[NH:8]2)(=[O:18])=[O:17]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: CNC
Solvent: CC(=O)O
Solvent: O
Product: CN(C)S(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 81 %

Procedure:
A mixture of 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% ethanolic dimethylamine is stirred at a temperature between 5° C. and 10° C. for 3 hours, and then allowed to stand for 16 hours. To the reaction mixture 5 ml of acetic acid and 60 ml of water are added, the separated crystals are filtered, washed with water and acetone, dried, dissolved in a slight amount of hot dimethyl sulfoxide and precipitated from this solution with water. Thus 3.80 g (81%) of N,N-dimethyl-1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: 318-332° C.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(O)(=O)C>[CH2:13]([N:21]1[C:22]([C:3]2[C:4](=[O:11])[C:5]3[C:10]([C:1](=[O:12])[CH:2]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:23][CH:24]=[C:25]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCn1cccc1
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: CC(=O)O
Product: CCCCCCCCn1c(C2=CC(=O)c3ccccc3C2=O)ccc1C1=CC(=O)c2ccccc2C1=O
Yield: 49 %

Procedure:
The same procedure as in Example 7 was followed by stirring 10 millimol of 1,4-naphthoquinone with 2.5 millimol of N-octylpyrrole in 40 ml of acetic acid at 50° C. for 5 hours. The 1-octyl-2,5-bis(1,4-naphthoquinon-2-yl)pyrrole was thus obtained in a yield of 49% after chromatography on a column of silica.