Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc([N+](=O)[O-])cc4)ccc31)C1CCC(C2)N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(N)cc4)ccc31)C1CCC(C2)N1
Yield: 95.9 %

Procedure:
A mixture of the product of step A (145 mg, 0.29 mmol), iron powder (82 mg, 1.45 mmol) and ammonium chloride (17 mg, 0.32 mmol) was taken up in ethanol (2.3 mL) and water (1.1 mL). The mixture was refluxed for 3 h then diluted with water and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated in vacuo to give tert-butyl 2-(4-aminophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (130 mg, 96%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.15 (s, 1H), 7.69-7.71 (m, 2H), 7.62 (d, J=9.3 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 6.60-6.65 (m, 2H), 5.24 (br s, 1H), 4.69 (br s, 1H), 4.04 (br s, 2H), 3.58 (s, 3H), 3.48 (br s, 1H), 2.48 (d, J=16.5 Hz, 1H), 2.12-2.32 (m, 2H), 1.89-1.97 (m, 1H), 1.52-1.64 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2nc3ccccc3nc2-c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
For example, in synthetic route `A2` of FIG. 2, 4,4'-difluorobenzil, 1,2-phenylenediamine and chloroform are charged together in a reaction vessel and stirred. A catalytic amount of trifluoroacetic acid is added slowly and the reaction mixture heated to about 50° C. with continued stirring. After about 16 h, the mixture is cooled to provide 2,3-bis(4-fluorophenyl)quinoxaline after removal of the chloroform. Recrystallization results 2,3-bis(4-fluorophenyl)quinoxaline having a melting point of 127-1290° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](/[CH:9]=[CH:10]/[C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[CH3:26]>[OH-].[Na+]>[OH:1][C:2]1[C:3]([CH3:26])=[CH:4][C:5](/[CH:9]=[CH:10]/[C:11](=[O:25])[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:18][CH:19]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)Cc1ccc(OCC(=O)/C=C/c2cc(C)c(O)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(/C=C/C(=O)COc2ccc(CC(=O)O)cc2)cc(C)c1O

Procedure:
Methyl (E)-4-[[4-(4-hydroxy-3,5-dimethylphenyl)2-oxo-3-butenyl]oxy]-benzene acetate (1.73 g) (0.00488 mole) is dissolved in 150 ml 0.1N NaOH and warmed on the steam bath. As soon as a temperature of 70° is reached the reaction mixture is removed from the bath and allowed to cool to 50°, at which point 1N HCl (17 ml) is added slowly. The precipitated solid is filtered off, washed with H2O, and recrystallized from HOAc-H2O to yield yellow crystals, 1.22 g (73%), mp 151°-153.5° C. Anal. for C20H20O5 : Calc. C 70.58, H 5.92; Fd. C 70.48, H 5.72.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18](N(OC)C)=[O:19])=[N:10]1.[CH3:24][Mg+].[Br-]>C1COCC1>[C:18]([C:11]1[C:12](=[O:17])[C:13]([O:15][CH3:16])=[CH:14][N:9]([C:3]2[CH:4]=[C:5]([I:8])[CH:6]=[CH:7][C:2]=2[F:1])[N:10]=1)(=[O:19])[CH3:24]
Reactant: C[Mg+]
Reactant: COc1cn(-c2cc(I)ccc2F)nc(C(=O)N(C)OC)c1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cn(-c2cc(I)ccc2F)nc(C(C)=O)c1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
To a mixture of 1-(2-fluoro-5-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxamide (4.33 g, 10.0 mmol) in THF (1.0 L) was added MeMgBr (1.0 M in THF, 20.0 mL, 20.0 mmol) at −78° C. under N2. The mixture was stirred at −78° C. for 2 h. The reaction was quenched with saturated NH4Cl aqueous solution at −78° C. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 0/100) and triturated with EtOAc/hexane to yield the title compound (3.58 g, 92% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.50 (3H, s), 3.80 (3H, s), 7.38 (1H, dd, J=11.0, 8.7 Hz), 7.95 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.15 (1H, dd, J=7.2, 2.3 Hz), 8.52 (1H, d, J=1.5 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:12]([NH:15]C(C)C)([CH3:14])[CH3:13]>CO>[CH3:13][CH:12]([NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:14]
Reactant: ClCCCOc1cccnc1
Reactant: CC(C)NC(C)C
Solvent: CO
Product: CC(C)NCCCOc1cccnc1
Temperature: 100 °C
Yield: 58.6 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (0.80 g, 4.66 mmol) was dissolved in methanol (25 mL) and added to diisopropylamine (25 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 100% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.531 g (58.6%) of a dark-brown oil. The compound exhibits a Ki of 8500 nM. The compound exhibits neurotransmitter release of 16 percent.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30]C(=O)OC)[C@H:9]([OH:29])[CH2:10][N:11]1[C@H:20]([C:21](=[O:28])[NH:22]OC(C)(C)C)[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[NH2:30][C@@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([OH:29])[CH2:10][N:11]1[C@H:20]([C:21]([NH:22][C:2]([CH3:7])([CH3:3])[CH3:1])=[O:28])[CH2:19][C@H:18]2[C@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12]1
Reactant: COC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NOC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 202.4 %

Procedure:
A suspension of 41.37 g of methyl (1S,2R)-[1-benzyl-3-[(3S,4aS,8aS)-3-tert-butoxycarbamoyl-octahydro-isoquinolin-2-yl]-2-hydroxy-propyl]-carbamate and 23.0 g of sodium hydroxide in 90 ml of ethanol and 90 ml of water was heated at reflux for 3.5 hours, diluted with 45 ml of water and cooled to 22° , and the separated solid was filtered off, washed with a 1:4 mixture of ethanol/water and dried, there being obtained 35.35 g (98%) of pure 2-[3(S)-amino-2(R)-hydroxy-4-phenyl-butyl]-N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide, m.p. 173°-175° C. IR (KBr): 3435m, br. (NH, OH), 1665s (C=O), 1562m (amide II).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([S:17][C:18]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([OH:31])[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:16]>>[CH2:15]([S:17][C:18]1([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([O:31][CH2:2][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]4)[CH:25]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)[CH3:16]
Reactant: CCSC1(c2cc(O)cc(F)c2)CCOCC1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: CCSC1(c2cc(F)cc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCOCC1
Yield: 40 %

Procedure:
Using a similar procedure to that described in Example 11, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with 4-ethylthio-4-(5-fluoro-3-hydroxyphenyl)tetrahydropyran to give 4-ethylthio-4-[5-fluoro-3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]tetrahydropyran in 40% yield, m.p. 73°-75° C.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1)#[CH:10].O>C(N(CC)CC)C.[Cu](I)I>[CH3:19][CH:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1)[CH3:18]
Reactant: Nc1ncccc1Br
Reactant: C#Cc1ccc(C(C)C)cc1
Agent: I[Cu]I
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C#Cc2cccnc2N)cc1
Yield: 46.6 %

Procedure:
A mixture of bis(triphenylphosphine)palladium(0)dichloride (0.811 g), 3-bromopyridin-2-amine (2 g), 1-ethynyl-4-isopropylbenzene (1.667 g) and copper iodide (I) (0.22 g) in triethylamine (38.6 mL) was heated under reflux. Water was added to the reaction mixture, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1273 mg) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)[OH:9])=[CH:6][CH:5]=[C:4]([CH3:16])[N:3]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:7]([C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([CH3:16])[N:3]=1
Reactant: Cc1ccc(C(O)c2cnnn2C)c(C)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)c2cnnn2C)c(C)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
A mixture containing (2,6-dimethylpyridin-3-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol (9.8 g, 44.9 mmol, Intermediate 54: step a) and manganese dioxide (18.8 g, 184 mmol) in dry dioxane (225 mL) was heated to 100° C. with stirring. After 1 h, the mixture was cooled to 40° C. The cooled mixture was filtered through a 2 cm pad of Celite rinsing with tetrahydrofuran (100 mL). The filtrate was concentrated to provide the title compound as an off-white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:37])[N:22]([C@@H:24]([C:32](=[O:36])[N:33]([CH3:35])[CH3:34])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O.ClCCl>[CH3:35][N:33]([CH3:34])[C:32]([C@H:24]([N:22]([CH3:23])[C:21](=[O:37])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:36]
Reactant: CN(C)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)C
Yield: 78.6 %

Procedure:
A solution of N-((1R)-1-(N-((1R)-1-(dimethylcarbamoyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (6.6 g, 12.8 mmol) in 50% trifluoroacetic acid/dichloromethane (15 ml) was stirred for 10 min. Then saturated sodium bicarbonate was added until pH 8 and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×20 ml) and the combined organic phases were washed with brine (10 ml), dried over magnesium sulfate and concentrated in vacuo to give 4.2 g of (2R)-N-((1R)-1-dimethylcarbamoyl-2-phenylethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](OC(=O)C)(=[O:11])C.O>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][CH:9]=[O:11]
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1cccs1
Solvent: O=CO
Solvent: O
Product: O=CNCCc1cccs1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-(2-thienyl)ethylamine (15.0 g, 118 mmol) was dissolved in formic acid (120 ml) while cooling with an water bath. The solution was cooled to 0° C. Acetic acid anhydride (45 ml was added dropwise. The reaction mixture was stirred at room temperature for 3 h. It was cooled to 0° C., and water (45 ml) was added dropwise. The mixture was stirred for 16 h, while it was warming up to room temperature. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 ml). The solution was washed with water (2×150 ml) and saturated sodium hydrogen carbonate solution (200 ml). It was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (180 g), using ethyl acetate/heptane (2:1) as eluent to give 14.30 g of N-(2-(2-thienyl)ethyl)formamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH:14]2[CH2:15][CH2:16][N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[CH2:18][CH2:19]2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)C2CCNCC2)cc1
Reactant: Cc1ccccc1Br
Product: Cc1ccccc1N1CCC(S(=O)(=O)c2ccc(C(C)(C)C)cc2)CC1
Yield: 44.1 %

Procedure:
Using the procedure from Example 7A, 4-[(4-tert-butylphenyl)sulfonyl]piperidine (100 mg, 0.36 mmol) was reacted with 2-bromotoluene (53 μl, 0.43 mmol) to afford the title compound (59 mg), a yellow solid, in 44% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[O:23]([C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[ClH:38]>>[ClH:1].[ClH:38].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:31]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Agent: Cl
Product: OC1(C(CN2CCN(Cc3cccc(Oc4ccccc4)c3)CC2)c2cccc(Cl)c2)CCCCC1

Procedure:
In an analogous manner to Example 117, 1-{1-(3-chlorophenyl)-2-[4-(3-phenoxnbenzyl)piperazin-1-yl]ethyl}cyclohexanol dihydrochloride was prepared from 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 1) and 3-phenoxybenzaldehyde. MS (ESI) m/z 505/507 ([M+H]+); HRMS: calcd for C31H37ClN2O2. 2.00 HCl, 576.2077; found (ESI_FT), 505.26266.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:10][CH2:9][S:8]1)=[O:5])[CH3:2].[Br:22]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[C:9]([Br:22])[S:8]1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)N=C1SCCN1c1cccc(C(F)(F)F)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N=c1sc(Br)cn1-c1cccc(C(F)(F)F)c1
Yield: 45.3 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)thiazolidine (1.6 g) and N-bromosuccinimide (2 g) in chloroform (50 ml) was refluxed for 10 hours. After cooling, the reaction mixture was washed with an aqueous sodium sulfite solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 0.9 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-bromothiazoline (Compound No. 30).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.Cl.[NH2:31][N:32]1[CH2:39][CH:38]2[CH:34]([CH2:35][CH2:36][CH2:37]2)[CH2:33]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][N:32]3[CH2:39][CH:38]4[CH2:37][CH2:36][CH2:35][CH:34]4[CH2:33]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Reactant: NN1CC2CCCC2C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(NN3CC4CCCC4C3)n2)cc1
Yield: 67 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 μL of triethylamine and 3-Amino-3-azabicyclo-[3,3,0]octane hydrochloride salt (19 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (34 mg, 67% yield.) MS/ES+: m/z=440.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:10]=1)=[O:5])C.[NH3:32]>CCO>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[N:9]2[CH:10]=[C:6]([C:4]([NH2:32])=[O:5])[N:7]=[N:8]2)(=[O:20])=[O:21])=[CH:23][CH:24]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1cn(-c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nn1
Reactant: N
Solvent: CCO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2cc(C(N)=O)nn2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 4 mL scintillation vial was charged with 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (synthesized according to general procedure G, 10 mg, 0.02 mmol) and 2 M NH3 in EtOH (1 mL). The reaction was heated to 100° C. and stirred overnight. The following day, the volatiles were removed in vacuo and the residue was purified by preparative TLC chromatography to afford 1-[2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-phenyl]-1H-[1,2,3]triazole-4-carboxylic acid amide: MS (ES) M+H expected 434.1, found 434.0.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[C:14]([OH:16])=[O:15])([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)Cl.[C:23]([O:26][CH2:27][CH3:28])(=[O:25])[CH3:24]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH:9]2[C:14]([O:16][C:4]1[CH:13]=[CH:12][C:24]([C:23]([O:26][CH2:27][CH3:28])=[O:25])=[CH:6][CH:5]=1)=[O:15])([O-:3])=[O:2]
Reactant: CCOC(C)=O
Reactant: O=C(O)C1CCCc2c1cccc2[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(OC(=O)C2CCCc3c2cccc3[N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In 50 ml of ethyl acetate was dissolved 5 g of 5-nitro-1,2,3,4-tetrahydro-1-naphthoic acid. After addition of 4.6 g of phosphorus pentachloride to the resulting solution at room temperature, the mixture was stirred for 30 minutes. The precipitates were removed by filtration and the filtrate was freed from ethyl acetate by distillation under reduced pressure. The residue was dissolved in 100 ml of fresh ethyl acetate. To the solution were added, with cooling, 4.1 g of p-ethoxycarbonylphenol and 2.5 g of triethylamine. The mixture was stirred for 24 hours. The reaction mixture was washed with a cold 5% sodium hydroxide solution and freed from the solvent by distillation to obtain 7.2 g (80% yield) of oily p-ethoxycarbonylphenyl 5-nitro-1,2,3,4-tetrahydro-1-naphthoate.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([N+:27]([O-])=O)[CH:3]=1.[H][H]>C(O)C.[Pt](=O)=O>[NH2:27][C:4]1[CH:3]=[C:2]([Cl:1])[CH:26]=[CH:25][C:5]=1[O:6][CH2:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:12][C@H:11]1[CH3:24])=[O:9]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Yield: 82.4 %

Procedure:
To a solution of 2-(4-chloro-2-nitro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.55 g, 1.3 mmol) in ethanol (25 mL) was added platinum dioxide on carbon (0.50 g, 5% on carbon). The reaction was subject to 35 psi hydrogen gas for 20 minutes. The reaction was then filtered through celite and the filtrate was concentrated to give the title compound (0.42 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=O.[C:13]1([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH2:7][C:21]2[S:20][C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:23][CH:22]=2)[CH:10]=1
Reactant: Cc1cc(C)c(C(=O)O)cc1Br
Reactant: c1ccc(-c2cccs2)cc1
Product: Cc1cc(C)c(Cc2ccc(-c3ccccc3)s2)cc1Br

Procedure:
2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100 ml), and thereto were added oxalyl chloride (6.8 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (200 ml). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2,4-dimethylbenzoate as pale yellow oil, which was used in the subsequent step without further purification. (2) To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g) and activated aluminum neutral oxide (120 g) was added dropwise bromine (9.25 ml) while stirring at room temperature. The mixture was stirred at room temperature for 8 hours, and diluted with diethyl ether (1000 ml). Insoluble materials were filtered off, and washed with diethyl ether (500 ml). The combined filtrate was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol (40 ml) to give methyl 5-bromo-2,4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H). (3) The above methyl 5-bromo-2,4-dimethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2,4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z 227/229 (M−H) (4) The above 5-bromo-2,4-dimethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 357/359 (M+H).